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Zhang M, Feng H, Du J, Chen S, Zhu L, Wang Y, Pan D, Chen G. Comparative Inhibitory Effects of Tacrolimus, Cyclosporine, and Rapamycin on Human Anti-Pig Xenogeneic Mixed Lymphocyte Reactions. Xenotransplantation 2024; 31:e12876. [PMID: 39031102 DOI: 10.1111/xen.12876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 05/16/2024] [Accepted: 06/14/2024] [Indexed: 07/22/2024]
Abstract
BACKGROUND Long-term immunosuppressive maintenance therapy is necessary to prevent the rejection of xenografts. However, it is still unclear which oral immunosuppressant is most suitable for pig-to-human xenotransplantation . METHODS A xenogeneic mixed lymphocyte reaction (MLR) system was established using peripheral blood mononuclear cells (PBMCs) isolated from wildtype (WT) or GTKO/CMAHKO/β4GalNT2KO (TKO) pigs as stimulator cells and human PBMCs as responder cells. Various concentrations of tacrolimus (Tac), cyclosporine (CsA), or rapamycin (Rapa) were added to the MLR system as interventions. The inhibitory effects of the three immunosuppressants on the proliferation and cytokine production of human T cells were studied and compared. The inhibitory effect of anti-CD154 mAb alone or in combination with Tac/CsA/Rapa on xenoreactive MLR was also investigated. RESULTS PBMCs from both WT and TKO pigs stimulated significant proliferation of human T cells. Tac had a strong inhibitory effect on human T-cell proliferation stimulated by pig PBMCs. CsA inhibited human T-cell proliferation in a typical dose-dependent manner. When Tac and CsA concentrations reached 5 and 200 ng/mL, respectively, the proliferation rates of CD3+/CD4+/CD8+ T cells were reduced almost to a negative level. Even at high concentrations, Rapa had only a moderate inhibitory effect on xenogeneic MLR. The inhibitory effects of these three immunosuppressants on xenogeneic T-cell responses were further confirmed by the detection of CD25 expression and supernatant cytokines (IL-2, IL-6, IFN-γ, TNF-α, IL-4, IL-10, and IL-17). Although anti-CD154 mAb monotherapy showed only moderate inhibitory effects on xenoreactive T-cell proliferation, low-dose anti-CD154 mAb combined with low-dose Tac, CSA, or Rapa could produce significant synergistic inhibitory effects. CONCLUSION Tac is more efficient than CsA or Rapa in inhibiting xenogeneic T-cell responses in vitro. If used in combination with anti-CD154 mAb, all the three immunosuppressants can achieve satisfactory synergistic inhibitory effects.
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Affiliation(s)
- Man Zhang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China
- NHC Key Laboratory of Organ Transplantation, Wuhan, China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Hao Feng
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China
- NHC Key Laboratory of Organ Transplantation, Wuhan, China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Jiaxiang Du
- Chengdu Clonorgan Biotechnology Co., Ltd, Chengdu, China
| | - Song Chen
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China
- NHC Key Laboratory of Organ Transplantation, Wuhan, China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Lan Zhu
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China
- NHC Key Laboratory of Organ Transplantation, Wuhan, China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Yi Wang
- Department of Organ Transplantation, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
- The Transplantation Institute of Hainan Medical University, Haikou, China
| | - Dengke Pan
- Chengdu Clonorgan Biotechnology Co., Ltd, Chengdu, China
| | - Gang Chen
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China
- NHC Key Laboratory of Organ Transplantation, Wuhan, China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
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Kim KJ, Ha J, Kim SW, Kim JE, Lee S, Choi HS, Hong N, Kong SH, Ahn SH, Park SY, Baek KH. Bone Loss after Solid Organ Transplantation: A Review of Organ-Specific Considerations. Endocrinol Metab (Seoul) 2024; 39:267-282. [PMID: 38693817 PMCID: PMC11066446 DOI: 10.3803/enm.2024.1939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 02/23/2024] [Accepted: 02/28/2024] [Indexed: 05/03/2024] Open
Abstract
This review article investigates solid organ transplantation-induced osteoporosis, a critical yet often overlooked issue, emphasizing its significance in post-transplant care. The initial sections provide a comprehensive understanding of the prevalence and multifactorial pathogenesis of transplantation osteoporosis, including factors such as deteriorating post-transplantation health, hormonal changes, and the impact of immunosuppressive medications. Furthermore, the review is dedicated to organ-specific considerations in transplantation osteoporosis, with separate analyses for kidney, liver, heart, and lung transplantations. Each section elucidates the unique challenges and management strategies pertinent to transplantation osteoporosis in relation to each organ type, highlighting the necessity of an organ-specific approach to fully understand the diverse manifestations and implications of transplantation osteoporosis. This review underscores the importance of this topic in transplant medicine, aiming to enhance awareness and knowledge among clinicians and researchers. By comprehensively examining transplantation osteoporosis, this study contributes to the development of improved management and care strategies, ultimately leading to improved patient outcomes in this vulnerable group. This detailed review serves as an essential resource for those involved in the complex multidisciplinary care of transplant recipients.
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Affiliation(s)
- Kyoung Jin Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Jeonghoon Ha
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sang Wan Kim
- Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
| | - Jung-Eun Kim
- Department of Molecular Medicine, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Sihoon Lee
- Department of Internal Medicine, Gachon University College of Medicine, Incheon, Korea
| | - Han Seok Choi
- Department of Internal Medicine, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, Goyang, Korea
| | - Namki Hong
- Department of Internal Medicine, Endocrine Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Sung Hye Kong
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Seong Hee Ahn
- Department of Endocrinology and Metabolism, Inha University Hospital, Inha University College of Medicine, Incheon, Korea
| | - So Young Park
- Department of Endocrinology and Metabolism, College of Medicine, Kyung Hee University, Seoul, Korea
| | - Ki-Hyun Baek
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - on Behalf of Metabolic Bone Disease Study Group of Korean Endocrine Society
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
- Department of Molecular Medicine, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Korea
- Department of Internal Medicine, Gachon University College of Medicine, Incheon, Korea
- Department of Internal Medicine, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, Goyang, Korea
- Department of Internal Medicine, Endocrine Research Institute, Yonsei University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
- Department of Endocrinology and Metabolism, Inha University Hospital, Inha University College of Medicine, Incheon, Korea
- Department of Endocrinology and Metabolism, College of Medicine, Kyung Hee University, Seoul, Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
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Park YA, Park J, Yee J, Gwak HS. Effects of CYP3A5 Genetic Polymorphisms on the Weight-adjusted through Concentration of Sirolimus in Renal Transplant Recipients: A Systematic Review and Meta-analysis. Curr Pharm Des 2024; 30:3108-3115. [PMID: 39171589 DOI: 10.2174/0113816128324199240730093415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 07/15/2024] [Accepted: 07/15/2024] [Indexed: 08/23/2024]
Abstract
BACKGROUND Sirolimus, one of the immunosuppressive drugs administered to renal transplant recipients, is metabolized by cytochrome P450 (CYP) 3A5. Accordingly, CYP3A5 polymorphism is a genetic factor affecting sirolimus pharmacokinetics (PK). Therefore, we conducted a systematic review and meta-analysis on the association between sirolimus PK and CYP3A5*3 polymorphism. METHODS We searched for studies published up to 13 June 2024 from PubMed, Embase, Cochrane Library, and Web of Science. We reviewed studies on the relationship between CYP3A5*3 polymorphism and weightadjusted trough concentration/dose (C0 /D) ratio and dosage of sirolimus in renal transplant recipients, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We evaluated mean differences (MDs) and 95% confidence intervals (CIs). RESULTS A total of seven studies were included. The weight-adjusted C0 /D ratio of sirolimus was significantly higher in patients with the CYP3A5*3/*3 rather than CYP3A5*1/*1 or CYP3A5*1/*3 genotype (MD 95.27 ng/mL per mg/kg; 95% CI: 58.06, 132.47; I2 = 74%; p < 0.00001). Also, the weight-adjusted dosage of sirolimus was significantly lower in patients with the CYP3A5*3/*3 rather than CYP3A5*1/*1 or CYP3A5*1/*3 genotype (MD -2.60 × 10-3 mg/kg; 95% CI: -4.52, -0.69; I2 = 44%; p = 0.008). CONCLUSION Our meta-analysis showed a significant effect for the CYP3A5*3 genotype on weight-adjusted C0 /D ratio and dosage of sirolimus in adult renal transplant recipients.
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Affiliation(s)
- Yoon-A Park
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Juyeong Park
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Jeong Yee
- School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, 16419, South Korea
| | - Hye Sun Gwak
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea
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Mane RR, Kale PP. The roles of HDAC with IMPDH and mTOR with JAK as future targets in the treatment of rheumatoid arthritis with combination therapy. JOURNAL OF COMPLEMENTARY & INTEGRATIVE MEDICINE 2023; 20:689-706. [PMID: 36409592 DOI: 10.1515/jcim-2022-0114] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Accepted: 07/19/2022] [Indexed: 06/16/2023]
Abstract
Various studies have shown that cytokines are important regulators in rheumatoid arthritis (RA). In synovial inflammation alteration of the enzyme HDAC, IMPDH enzyme, mTOR pathway, and JAK pathway increase cytokine level. These increased cytokine levels are responsible for the inflammation in RA. Inflammation is a physiological and normal reaction of the immune system against dangerous stimuli such as injury and infection. The cytokine-based approach improves the treatment of RA. To reach this goal, various researchers and scientists are working more aggressively by using a combination approach. The present review of combination therapy provides essential evidence about the possible synergistic effect of combinatorial agents. We have focused on the effects of HDAC inhibitor with IMPDH inhibitor and mTOR inhibitor with JAK inhibitor in combination for the treatment of RA. Combining various targeted strategies can be helpful for the treatment of RA.
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Affiliation(s)
- Reshma Rajendra Mane
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Mumbai, India
| | - Pravin Popatrao Kale
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Mumbai, India
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de Faria LM, Nobre V, Guardão LRDO, Souza CM, de Souza AD, Estrella DDR, Pessoa BP, Corrêa RA. Factors associated with pulmonary infection in kidney and kidney-pancreas transplant recipients: a case-control study. J Bras Pneumol 2023; 49:e20220419. [PMID: 37729335 PMCID: PMC10578948 DOI: 10.36416/1806-3756/e20220419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 07/15/2023] [Indexed: 09/22/2023] Open
Abstract
OBJECTIVE To evaluate the etiology of and factors associated with pulmonary infection in kidney and kidney-pancreas transplant recipients. METHODS This was a single-center case-control study conducted between December of 2017 and March of 2020 at a referral center for kidney transplantation in the city of Belo Horizonte, Brazil. The case:control ratio was 1:1.8. Cases included kidney or kidney-pancreas transplant recipients hospitalized with pulmonary infection. Controls included kidney or kidney-pancreas transplant recipients without pulmonary infection and matched to cases for sex, age group, and donor type (living or deceased). RESULTS A total of 197 patients were included in the study. Of those, 70 were cases and 127 were controls. The mean age was 55 years (for cases) and 53 years (for controls), with a predominance of males. Corticosteroid use, bronchiectasis, and being overweight were associated with pulmonary infection risk in the multivariate logistic regression model. The most common etiologic agent of infection was cytomegalovirus (in 14.3% of the cases), followed by Mycobacterium tuberculosis (in 10%), Histoplasma capsulatum (in 7.1%), and Pseudomonas aeruginosa (in 7.1%). CONCLUSIONS Corticosteroid use, bronchiectasis, and being overweight appear to be risk factors for pulmonary infection in kidney/kidney-pancreas transplant recipients, endemic mycoses being prevalent in this population. Appropriate planning and follow-up play an important role in identifying kidney and kidney-pancreas transplant recipients at risk of pulmonary infection.
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Affiliation(s)
- Leonardo Meira de Faria
- . Faculdade Ciências Médicas de Minas Gerais - FCMMG - Belo Horizonte (MG) Brasil
- . Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical, Universidade Federal de Minas Gerais - UFMG - Belo Horizonte (MG) Brasil
- . Hospital Felício Rocho, Belo Horizonte (MG) Brasil
| | - Vandack Nobre
- . Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical, Universidade Federal de Minas Gerais - UFMG - Belo Horizonte (MG) Brasil
| | | | | | - Amanda Damasceno de Souza
- . Programa de Pós-Graduação em Tecnologia da Informação e Comunicação e Gestão do Conhecimento - PPGTICGC - Universidade FUMEC, Belo Horizonte (MG) Brasil
| | - Deborah dos Reis Estrella
- . Hospital Felício Rocho, Belo Horizonte (MG) Brasil
- . Programa de Pós-Graduação de Ciências Aplicadas em Saúde do Adulto, Universidade Federal de Minas Gerais - UFMG - Belo Horizonte (MG) Brasil
| | - Bruno Porto Pessoa
- . Faculdade Ciências Médicas de Minas Gerais - FCMMG - Belo Horizonte (MG) Brasil
| | - Ricardo Amorim Corrêa
- . Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical, Universidade Federal de Minas Gerais - UFMG - Belo Horizonte (MG) Brasil
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Mir SA, Dar A, Alshehri SA, Wahab S, Hamid L, Almoyad MAA, Ali T, Bader GN. Exploring the mTOR Signalling Pathway and Its Inhibitory Scope in Cancer. Pharmaceuticals (Basel) 2023; 16:1004. [PMID: 37513916 PMCID: PMC10384750 DOI: 10.3390/ph16071004] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 07/11/2023] [Accepted: 07/12/2023] [Indexed: 07/30/2023] Open
Abstract
Mechanistic target of rapamycin (mTOR) is a protein kinase that regulates cellular growth, development, survival, and metabolism through integration of diverse extracellular and intracellular stimuli. Additionally, mTOR is involved in interplay of signalling pathways that regulate apoptosis and autophagy. In cells, mTOR is assembled into two complexes, mTORC1 and mTORC2. While mTORC1 is regulated by energy consumption, protein intake, mechanical stimuli, and growth factors, mTORC2 is regulated by insulin-like growth factor-1 receptor (IGF-1R), and epidermal growth factor receptor (EGFR). mTOR signalling pathways are considered the hallmark in cancer due to their dysregulation in approximately 70% of cancers. Through downstream regulators, ribosomal protein S6 kinase β-1 (S6K1) and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), mTORC1 influences various anabolic and catabolic processes in the cell. In recent years, several mTOR inhibitors have been developed with the aim of treating different cancers. In this review, we will explore the current developments in the mTOR signalling pathway and its importance for being targeted by various inhibitors in anti-cancer therapeutics.
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Affiliation(s)
- Suhail Ahmad Mir
- Department of Pharmaceutical Sciences, University of Kashmir, Hazratbal, Srinagar 190006, Jammu and Kashmir, India
| | - Ashraf Dar
- Department of Biochemistry, University of Kashmir, Hazratbal, Srinagar 190006, Jammu and Kashmir, India
| | - Saad Ali Alshehri
- Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha 62529, Saudi Arabia
| | - Shadma Wahab
- Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha 62529, Saudi Arabia
| | - Laraibah Hamid
- Department of Zoology, University of Kashmir, Hazratbal, Srinagar 190006, Jammu and Kashmir, India
| | - Mohammad Ali Abdullah Almoyad
- Department of Basic Medical Sciences, College of Applied Medical Sciences in Khamis Mushyt, King Khalid University, Abha 61412, Saudi Arabia
| | - Tabasum Ali
- Department of Pharmaceutical Sciences, University of Kashmir, Hazratbal, Srinagar 190006, Jammu and Kashmir, India
| | - Ghulam Nabi Bader
- Department of Pharmaceutical Sciences, University of Kashmir, Hazratbal, Srinagar 190006, Jammu and Kashmir, India
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Villa A, Kuten-Shorrer M. Pathogenesis of Oral Toxicities Associated with Targeted Therapy and Immunotherapy. Int J Mol Sci 2023; 24:ijms24098188. [PMID: 37175898 PMCID: PMC10179284 DOI: 10.3390/ijms24098188] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 04/04/2023] [Accepted: 04/28/2023] [Indexed: 05/15/2023] Open
Abstract
Targeted therapy and immunotherapy have redefined cancer treatment. While they have enhanced tumor response and improved survival rates in many cancer types, toxicities continue to occur, and these often involve the oral cavity. Broadly reported as "mucositis" or "stomatitis," oral toxicities induced by targeted therapies differ clinically and mechanistically from those associated with conventional chemotherapy. Manifesting primarily as mucosal lesions, salivary gland hypofunction, or orofacial neuropathies, these oral toxicities may nonetheless lead to significant morbidity and impact patients' quality of life, thereby compromising clinical outcomes. We conclude that familiarity with the spectrum of associated toxicities and understanding of their pathogenesis represent important areas of clinical research and may lead to better characterization, prevention, and management of these adverse events.
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Affiliation(s)
- Alessandro Villa
- Oral Medicine, Oral Oncology and Dentistry, Miami Cancer Institute, Baptist Health South Florida, Miami, FL 33176, USA
- The Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33176, USA
- Department of Orofacial Sciences, University of California San Francisco, San Francisco, CA 94143, USA
| | - Michal Kuten-Shorrer
- Eastman Institute for Oral Health, University of Rochester Medical Center, Rochester, New York, NY 14642, USA
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Efficacy and Safety of Topical Mechanistic Target of Rapamycin Inhibitors for Facial Angiofibromas in Patients with Tuberous Sclerosis Complex: A Systematic Review and Network Meta-Analysis. Biomedicines 2022; 10:biomedicines10040826. [PMID: 35453576 PMCID: PMC9025300 DOI: 10.3390/biomedicines10040826] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 03/30/2022] [Accepted: 03/30/2022] [Indexed: 02/04/2023] Open
Abstract
Previous studies have suggested that the topical mechanistic target of rapamycin (mTOR) inhibitors may be effective in treating facial angiofibromas in patients with tuberous sclerosis complex (TSC). Various concentrations of topical sirolimus for TSC have been tested, but their comparative efficacy and safety remained unclear. To assess the effects of topical mTOR inhibitors in treating facial angiofibromas, we conducted a systematic review and network meta-analysis (NMA) and searched MEDLINE, Embase, and Cochrane Library for relevant randomized controlled trials on 14 February 2022. The Cochrane Collaboration tool was used to assess the risk of bias of included trials. Our outcomes were clinical improvement and severe adverse events leading to withdrawal. We included three trials on 261 TSC patients with facial angiofibromas. The NMA found when compared with placebo, facial angiofibromas significantly improved following the application of various concentrations of topical sirolimus (risk ratio being 3.87, 2.70, 4.43, and 3.34 for 0.05%, 0.1%, 0.2%, and 1%, respectively). When compared with placebo, all concentrations of topical sirolimus did not differ in severe adverse events leading to withdrawal. The ranking analysis suggested topical sirolimus 0.2% as the most effective drug. In conclusion, topical sirolimus 0.05–1% are effective and safe in treating facial angiofibromas in patients with TSC, with topical sirolimus 0.2% being the most effective.
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Khader A, Bokhari R, Hakimelahi R, Scheirey C, Afnan J, Braschi-Amirfarzan M, Thomas R. A radiologist’s guide to novel anticancer therapies in the era of precision medicine. Eur J Radiol Open 2022; 9:100406. [PMID: 35265736 PMCID: PMC8899228 DOI: 10.1016/j.ejro.2022.100406] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 02/14/2022] [Accepted: 02/15/2022] [Indexed: 12/13/2022] Open
Abstract
Novel anticancer agents have replaced conventional chemotherapy as first line agents for many cancers, with continued new and expanding indications. Small molecule inhibitors act on cell surface or intracellular targets and prevent the downstream signaling that would otherwise permit tumor growth and spread. Anticancer antibodies can be directed against growth factors or may be immunotherapeutic agents. The latter act by inhibiting mechanisms that cancer cells use to evade the immune system. Hormonal agents act by decreasing levels of hormones that are necessary for the growth of certain cancer cells. Cancer therapy protocols often include novel anticancer agents and conventional chemotherapy used successively or in combination, in order to maximize survival and minimize morbidity. A working knowledge of anti-cancer drug classification will aid the radiologist in assessing response on imaging.
Novel anticancer agents include small molecule inhibitors, antibodies and hormones. These agents are predominantly cytostatic and inhibit factors that provide a survival advantage to tumor cells. Modern cancer therapy employs a combination of novel anticancer agents and conventional chemotherapy. It is essential for radiologists to have a broad understanding of these agents and their mechanisms of action.
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Abstract
Mechanistic target of rapamycin (mTOR) inhibitors are macrocyclic lactone antibiotics derived from Streptomyces hygroscopicus that prevent T lymphocyte activation and B cell differentiation. Unlike calcineurin inhibitors (CNIs) that inhibit cytokine production, mTOR inhibitors block the cytokine signal transduction to arrest cells in the G1 to S phase. This class of drugs is commonly used for post-transplantation and cancer management because of its immunosuppressive and antiproliferative properties, respectively. The potential uses of mTOR inhibitors are heavily explored because of their impact on cell growth and proliferation. However, mTOR inhibitors have a broad range of effects that can result in adverse reactions, but side effects can occur with other immunosuppressive agents as well. Thus, the performance of mTOR inhibitors is compared to the outcomes and adverse effects of other immunosuppressive drugs or the combination of other immunosuppressants and mTOR inhibitors. Because mTOR regulates many downstream pathways, mTOR inhibitors can affect these pathways to manage various diseases. Sirolimus (rapamycin) is approved by the Food and Drug Administration (FDA) to treat post-renal transplantation and lymphangioleiomyomatosis (LAM). Everolimus is approved by the FDA to treat postmenopausal advanced hormone receptor-positive, HER2-negative breast cancer in women, progressive neuroendocrine tumors of pancreatic origin (PNET), advanced renal cell carcinoma (RCC), renal angiomyolipoma (AML) and tuberous sclerosis complex (TSC), and subependymal giant cell astrocytoma (SEGA) associated with TSC as well as renal and liver transplantation. Temsirolimus is approved by the FDA to treat advanced RCC. Opportunities to use mTOR inhibitors as therapy for other transplantation, metabolic disease, and cancer management are being researched. mTOR inhibitors are often called proliferation signal inhibitors (PSIs) because of their effects on proliferation pathways.
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Affiliation(s)
- Denise Wang
- Mount Sinai Icahn School of Medicine, New York, NY, USA.
| | - Howard J Eisen
- Pennsylvania State University College of Medicine/Milton S. Hershey Medical Center, Hershey, PA, USA
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Bikhet M, Iwase H, Yamamoto T, Jagdale A, Foote JB, Ezzelarab M, Anderson DJ, Locke JE, Eckhoff DE, Hara H, Cooper DKC. What Therapeutic Regimen Will Be Optimal for Initial Clinical Trials of Pig Organ Transplantation? Transplantation 2021; 105:1143-1155. [PMID: 33534529 DOI: 10.1097/tp.0000000000003622] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
We discuss what therapeutic regimen might be acceptable/successful in the first clinical trial of genetically engineered pig kidney or heart transplantation. As regimens based on a calcineurin inhibitor or CTLA4-Ig have proved unsuccessful, the regimen we administer to baboons is based on induction therapy with antithymocyte globulin, an anti-CD20 mAb (Rituximab), and cobra venom factor, with maintenance therapy based on blockade of the CD40/CD154 costimulation pathway (with an anti-CD40 mAb), with rapamycin, and a corticosteroid. An anti-inflammatory agent (etanercept) is administered for the first 2 wk, and adjuvant therapy includes prophylaxis against thrombotic complications, anemia, cytomegalovirus, and pneumocystis. Using this regimen, although antibody-mediated rejection certainly can occur, we have documented no definite evidence of an adaptive immune response to the pig xenograft. This regimen could also form the basis for the first clinical trial, except that cobra venom factor will be replaced by a clinically approved agent, for example, a C1-esterase inhibitor. However, none of the agents that block the CD40/CD154 pathway are yet approved for clinical use, and so this hurdle remains to be overcome. The role of anti-inflammatory agents remains unproven. The major difference between this suggested regimen and those used in allotransplantation is the replacement of a calcineurin inhibitor with a costimulation blockade agent, but this does not appear to increase the complications of the regimen.
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Affiliation(s)
- Mohamed Bikhet
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Hayato Iwase
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Takayuki Yamamoto
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Abhijit Jagdale
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Jeremy B Foote
- Department of Microbiology and Animal Resources Program, University of Alabama at Birmingham, Birmingham, AL
| | - Mohamed Ezzelarab
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Douglas J Anderson
- Division of Transplantation, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Jayme E Locke
- Division of Transplantation, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Devin E Eckhoff
- Division of Transplantation, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Hidetaka Hara
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - David K C Cooper
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
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12
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Kelleher KJ, Russell J, Killeen OG, Leahy TR. Treatment-recalcitrant laryngeal sarcoidosis responsive to sirolimus. BMJ Case Rep 2020; 13:13/8/e235372. [PMID: 32847880 DOI: 10.1136/bcr-2020-235372] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
A 15-year-old girl presented with gradual-onset dysphonia and dysphagia. Laryngoscopy revealed significant supraglottic airway obstruction with swelling of both the epiglottis and arytenoids. After emergency tracheostomy, biopsy of the epiglottis revealed lymphoid hyperplasia with focal non-necrotising granulomata, leading to a presumed diagnosis of laryngeal sarcoidosis. Treatment with prednisolone and methotrexate produced minimal clinical improvement. A switch to sirolimus was followed by significant reduction in the laryngeal swelling, allowing decannulation of the tracheostomy. Treatment with sirolimus should be considered as a steroid sparing agent in laryngeal sarcoidosis, particularly in the presence of lymphoid hyperplasia on biopsy.
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Affiliation(s)
| | - John Russell
- Paediatric Otorhinolaryngology, CHI at Crumlin, Dublin, Ireland
| | - Orla G Killeen
- Paediatric Rheumatology, CHI at Crumlin, Dublin, Ireland.,Department of Paediatrics, University College Dublin, Dublin, Ireland
| | - Timothy Ronan Leahy
- Paediatric ID and Immunology, CHI at Crumlin, Dublin, Ireland .,Department of Paediatrics, University of Dublin, Trinity College, Dublin, Ireland
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13
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Anastasilakis AD, Tsourdi E, Makras P, Polyzos SA, Meier C, McCloskey EV, Pepe J, Zillikens MC. Bone disease following solid organ transplantation: A narrative review and recommendations for management from The European Calcified Tissue Society. Bone 2019; 127:401-418. [PMID: 31299385 DOI: 10.1016/j.bone.2019.07.006] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 07/07/2019] [Accepted: 07/08/2019] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Solid organ transplantation is an established therapy for end-stage organ failure. Both pre-transplantation bone disease and immunosuppressive regimens result in rapid bone loss and increased fracture rates. METHODS The European Calcified Tissue Society (ECTS) formed a working group to perform a systematic review of existing literature on the consequences of end-stage kidney, liver, heart, and lung disease on bone health. Moreover, we assessed the characteristics of post-transplant bone disease and the skeletal effects of immunosuppressive agents and aimed to provide recommendations for the prevention and treatment of transplantation-related osteoporosis. RESULTS Characteristics of bone disease may differ depending on the organ that fails, but patients awaiting solid organ transplantation frequently depict a wide spectrum of bone and mineral abnormalities. Common features are a decreased bone mass and impaired bone strength with consequent high fracture risk, all of which are aggravated in the early post-transplantation period. CONCLUSION Both the underlying disease leading to end-stage organ failure and the immunosuppression regimens implemented after successful organ transplantation have detrimental effects on bone mass, quality and strength. Given existing ample data confirming the high frequency of bone disease in patients awaiting solid organ transplantation, we recommend that all transplant candidates should be assessed for osteoporosis and fracture risk and, if indicated, treated before and after transplantation. Since bone loss in the early post-transplantation period occurs in virtually all solid organ recipients and is associated with glucocorticoid administration, the goal should be to use the lowest possible dose and to taper and withdraw glucocorticoids as early as possible.
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Affiliation(s)
| | - Elena Tsourdi
- Department of Medicine III, Technische Universität Dresden Medical Center, Dresden, Germany; Center for Healthy Aging, Technische Universität Dresden Medical Center, Dresden, Germany
| | - Polyzois Makras
- Department of Endocrinology and Diabetes, 251 Hellenic Force & VA General Hospital, Athens, Greece
| | - Stergios A Polyzos
- First Department of Pharmacology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Christian Meier
- Division of Endocrinology, Diabetology and Metabolism, University Hospital and University of Basel, Switzerland
| | - Eugene V McCloskey
- Centre for Metabolic Bone Diseases, University of Sheffield, Sheffield, UK; Centre for Integrated research in Musculoskeletal Ageing (CIMA), Mellanby Centre for Bone Research, University of Sheffield, Sheffield, UK
| | - Jessica Pepe
- Department of Internal Medicine and Medical Disciplines, "Sapienza" University, Rome, Italy
| | - M Carola Zillikens
- Bone Center, Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands.
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14
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Lopez-Soler RI, Patel SK, Lyubarova R, Pashkovetsky E, Wang S, Schuster D, Chandolias N, Conti D. Pericardial Effusion Associated With Sirolimus Use After Renal Transplantation: A Single-Center Case Series. Transplant Proc 2019; 51:1739-1743. [DOI: 10.1016/j.transproceed.2019.04.043] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Accepted: 04/22/2019] [Indexed: 01/25/2023]
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15
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Lee C, Guo H, Klinngam W, Janga SR, Yarber F, Peddi S, Edman MC, Tiwari N, Liu S, Louie SG, Hamm-Alvarez SF, MacKay JA. Berunda Polypeptides: Biheaded Rapamycin Carriers for Subcutaneous Treatment of Autoimmune Dry Eye Disease. Mol Pharm 2019; 16:3024-3039. [PMID: 31095909 DOI: 10.1021/acs.molpharmaceut.9b00263] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The USFDA-approved immunosuppressive drug rapamycin (Rapa), despite its potency, is limited by poor bioavailability and a narrow therapeutic index. In this study, we sought to improve bioavailability of Rapa with subcutaneous (SC) administration and to test its therapeutic feasibility and practicality in a murine model of Sjögren's syndrome (SS), a systemic autoimmune disease with no approved therapies. To improve its therapeutic index, we formulated Rapa with a carrier termed FAF, a fusion of the human cytosolic FK506-binding protein 12 (FKBP12) and an elastin-like polypeptide (ELP). The resulting 97 kDa FAF (i) has minimal burst release, (ii) is "humanized", (iii) is biodegradable, (iv) solubilizes two Rapa per FAF, and (v) avoids organic solvents or amphiphilic carriers. Demonstrating high stability, FAF remained soluble and monodisperse with a hydrodynamic radius of 8 nm at physiological temperature. A complete pharmacokinetic (PK) analysis of FAF revealed that the bioavailability of SC FAF was 60%, with significantly higher blood concentration during the elimination phase compared to IV FAF. The plasma concentration of Rapa delivered by FAF was 8-fold higher with a significantly increased plasma-to-whole blood ratio relative to free Rapa, 24 h after injection. To evaluate therapeutic effects, FAF-Rapa was administered SC every other day for 2 weeks to male non-obese diabetic (NOD) mice, which develop an SS-like autoimmune-mediated lacrimal gland (LG) inflammation and other characteristic features of SS. Both FAF-Rapa and free Rapa exhibited immunomodulatory effects by significantly suppressing lymphocytic infiltration, gene expression of IFN-γ, MHC II, type I collagen and IL-12a, and cathepsin S (CTSS) activity in LG compared to controls. Serum chemistry and histopathological analyses in major organs revealed no apparent toxicity of FAF-Rapa. Given its improved PK and equipotent therapeutic efficacy compared to free Rapa, FAF-Rapa is of further interest for systemic treatments for autoimmune diseases like SS.
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Affiliation(s)
- Changrim Lee
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy , University of Southern California , Los Angeles , California 90089 , United States
| | - Hao Guo
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy , University of Southern California , Los Angeles , California 90089 , United States
| | - Wannita Klinngam
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy , University of Southern California , Los Angeles , California 90089 , United States
| | - Srikanth R Janga
- Department of Ophthalmology, USC Roski Eye Institute, Keck School of Medicine , University of Southern California , Los Angeles , California 90089 , United States
| | - Frances Yarber
- Department of Ophthalmology, USC Roski Eye Institute, Keck School of Medicine , University of Southern California , Los Angeles , California 90089 , United States
| | - Santosh Peddi
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy , University of Southern California , Los Angeles , California 90089 , United States
| | - Maria C Edman
- Department of Ophthalmology, USC Roski Eye Institute, Keck School of Medicine , University of Southern California , Los Angeles , California 90089 , United States
| | - Nishant Tiwari
- Department of Pathology, Keck School of Medicine , University of Southern California , Los Angeles , California 90089 , United States
| | - Siyu Liu
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy , University of Southern California , Los Angeles , California 90089 , United States
| | - Stan G Louie
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy , University of Southern California , Los Angeles , California 90089 , United States
| | - Sarah F Hamm-Alvarez
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy , University of Southern California , Los Angeles , California 90089 , United States.,Department of Ophthalmology, USC Roski Eye Institute, Keck School of Medicine , University of Southern California , Los Angeles , California 90089 , United States
| | - J Andrew MacKay
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy , University of Southern California , Los Angeles , California 90089 , United States.,Department of Ophthalmology, USC Roski Eye Institute, Keck School of Medicine , University of Southern California , Los Angeles , California 90089 , United States.,Department of Biomedical Engineering, Viterbi School of Engineering , University of Southern California , Los Angeles , California 90089 , United States
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16
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Pan GH, Chen Z, Xu L, Zhu JH, Xiang P, Ma JJ, Peng YW, Li GH, Chen XY, Fang JL, Guo YH, Zhang L, Liu LS. Low-dose tacrolimus combined with donor-derived mesenchymal stem cells after renal transplantation: a prospective, non-randomized study. Oncotarget 2017; 7:12089-101. [PMID: 26933811 PMCID: PMC4914271 DOI: 10.18632/oncotarget.7725] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2015] [Accepted: 01/29/2016] [Indexed: 12/22/2022] Open
Abstract
Calcineurin inhibitors, including tacrolimus, are largely responsible for advances in allotransplantation. However, the nephrotoxicity associated with these immunosuppressants impairs patients' long-term survival after renal allograft. Therefore, novel regimens that minimize or even eliminate calcineurin inhibitors could improve transplantation outcomes. In this pilot study, we investigated the use of low-dose tacrolimus in combination with mesenchymal stem cells (MSCs), which are immunosuppressive and prolong allograft survival in experimental organ transplant models. Donor-derived, bone marrow MSCs combined with a sparing dose of tacrolimus (0.04-0.05 mg/kg/day) were administered to 16 de novo living-related kidney transplant recipients; 16 other patients received a standard dose of tacrolimus (0.07-0.08 mg/kg/day). The safety of MSC infusion, acute rejection, graft function, graft survival, and patient survival were evaluated over ≥24 months following kidney transplantation. All patients survived and had stable renal function at the 24 month follow-up. The combination of low-dose tacrolimus and MSCs was as effective as standard dose tacrolimus in maintaining graft survival at least 2 years after transplantation. In addition, both groups had similar urea, urine protein, urinary RBC, urinary WBC, 24-h urine protein, and creatinine clearance rates from 7 days to 24 months after transplantation. Furthermore, no differences in the proportion of lymphocytes, CD19, CD3, CD34, CD38, and natural killer cells were detected between the control and experimental groups. None of the MSC recipients experienced immediate or long-term toxicity from the treatment. This preliminary data suggests that the addition of MSCs permits the use of lower dosages of nephrotoxic calcineurin inhibitors following renal transplantation.
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Affiliation(s)
- Guang-Hui Pan
- The Transplantation Centre, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Zheng Chen
- The Transplantation Centre, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Lu Xu
- The Transplantation Centre, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Jing-Hui Zhu
- The Transplantation Centre, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Peng Xiang
- Center for Stem Cell Biology and Tissue Engineering, SunYat-sen University, Guangzhou, Guangdong, China
| | - Jun-Jie Ma
- The Transplantation Centre, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Yan-Wen Peng
- Center for Stem Cell Biology and Tissue Engineering, SunYat-sen University, Guangzhou, Guangdong, China
| | - Guang-Hui Li
- The Transplantation Centre, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Xiao-Yong Chen
- Center for Stem Cell Biology and Tissue Engineering, SunYat-sen University, Guangzhou, Guangdong, China
| | - Jia-Li Fang
- The Transplantation Centre, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Yu-He Guo
- The Transplantation Centre, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Lei Zhang
- The Transplantation Centre, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Long-Shan Liu
- Laboratory of General Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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17
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Ji YD, Aboalela A, Villa A. Everolimus-associated stomatitis in a patient who had renal transplant. BMJ Case Rep 2016; 2016:bcr-2016-217513. [PMID: 27797804 DOI: 10.1136/bcr-2016-217513] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Everolimus is used as an immunosuppressant in renal allograft transplant rejection and in metastatic breast cancer treatment. One side effect of everolimus is stomatitis, referred to as mammalian target of rapamycin inhibitor-associated stomatitis. This side effect can affect treatment course and contribute to discontinuation of therapy or dose reduction, previously reported in the treatment of metastatic breast cancer. Here, we present a case of everolimus-associated stomatitis with a novel management method with intralesional triamcinolone that allows for continuous course of everolimus.
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Affiliation(s)
- Yisi D Ji
- Harvard School of Dental Medicine, Boston, Massachusetts, USA
| | - Ali Aboalela
- Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Alessandro Villa
- Department of Oral Medicine and Dentistry, Brigham and Women's Hospital, Boston, Massachusetts, USA
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18
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Bagheri L, Hami M, Mojahedi MJ, Ghorban Sabbagh M, Ayatollahi H. Association of metabolic syndrome with serum fibroblast growth factor 21 in kidney transplanted patients. J Renal Inj Prev 2016; 5:79-84. [PMID: 27471739 PMCID: PMC4962674 DOI: 10.15171/jrip.2016.17] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Accepted: 04/14/2016] [Indexed: 12/23/2022] Open
Abstract
INTRODUCTION Fibroblast growth factor 21 (FGF21) is a metabolic regulator with multiple beneficial effects on glucose and lipid homeostasis and insulin sensitivity. OBJECTIVES The aim of this study was to investigate the relation between the serum level of FGF21 with and metabolic syndrome (MS) in kidney transplant recipients. PATIENTS AND METHODS We performed a cross-sectional study on 86 stable renal transplant recipients to detect possible relation between serum FGF21 level and MS during October 2014 and Mach 2015. Patients with past history of diabetes mellitus were excluded. RESULTS There were 43 patients in each group with and without MS. Totally, they were 52 (60.5%) male and 34 (39.5%) female. The mean age of the MS group was significantly higher than that of non-MS group. There was not significant difference between mean serum creatinine level and glomerular filtration rate (GFR) between two groups (P > 0.05). The MS patients had higher weight and body mass index (BMI) (P < 0.05). The prevalence of BMI >25 kg/m(2) in MS group was 25 (58.8%) versus non-MS group that only 10 (23.3%) had this condition (P < 0.05). The mean of FGF21 level in MS and non-MS groups was 1.23 ± 0.67 ng/l and 1.18 ± 0.71 ng/l, respectively (P > 0.05). There was not significant difference of serum FGF21 level between MS and non-MS patients (P > 0.05). CONCLUSION While the elevated serum FGF21 level was found in subjects with insulin resistant states, however, this study revealed that serum FGF21 levels were not significantly increased in renal transplanted recipients with MS as compared with non-MS group.
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Affiliation(s)
- Leila Bagheri
- Kidney Transplantation Complications Research Center, Montaserieh Hospital, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Maryam Hami
- Kidney Transplantation Complications Research Center, Montaserieh Hospital, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad-Javad Mojahedi
- Kidney Transplantation Complications Research Center, Montaserieh Hospital, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahin Ghorban Sabbagh
- Kidney Transplantation Complications Research Center, Montaserieh Hospital, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hosein Ayatollahi
- Hematology and Blood Banking Department, Cancer Molecular Pathology Research Center, Ghaem Hospital, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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19
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Abstract
Kidney transplantation is the best treatment for end-stage renal disease, but its implementation is limited by organ shortage and immune rejection. Side effects of current immunosuppressive drugs, such as nephrotoxicity, opportunistic infection, and tumorigenic potential, influence long-term graft outcomes. In recent years, continued research and subsequent discoveries concerning the properties and potential utilization of mesenchymal stem cells (MSCs) have aroused considerable interest and expectations. Biological characteristics of MSCs, including multi-lineage differentiation, homing potential, paracrine effect and immunomodulation, have opened new horizons for applications in kidney transplantation. However, many studies have shown that the biological activity of MSCs depends on internal inflammatory conditions, and the safety and efficacy of the clinical application of MSCs remain controversial. This review summarizes the findings of a large number of studies and aims to provide an objective viewpoint based on a comprehensive analysis of the presently established benefits and obstacles of implementing MSC-based therapy in kidney transplantation, and to promote its clinical translation.
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Affiliation(s)
- Cheng Chen
- Department of Urology, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, 215006, Jiangsu, PR China
| | - Jianquan Hou
- Department of Urology, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, 215006, Jiangsu, PR China.
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20
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Su VC, Greanya ED, Ensom MHH. Impact of Mycophenolate Mofetil Dose Reduction on Allograft Outcomes in Kidney Transplant Recipients on Tacrolimus-Based Regimens: A Systematic Review. Ann Pharmacother 2015; 45:248-57. [PMID: 21304036 DOI: 10.1345/aph.1p456] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
OBJECTIVE To systematically evaluate the clinical consequences of mycophenolate dose reduction in renal transplant recipients on tacrolimus-based regimens. DATA SOURCES PubMed (1949-July 2010), EMBASE (1980-July 2010), Cochrane Database of Systematic Reviews, International Pharmaceutical Abstracts, and Web of Science were searched using the terms mycophenolate mofetil, tacrolimus, dose reduction, and kidney and/or renal transplant. References from publications identified were reviewed. STUDY SELECTION AND DATA EXTRACTION Studies reporting on rejection rate, allograft survival, or renal function were included and ranked according to the US Preventive Services Task Force classification; excluded were studies that were dose-finding or used cyclosporine only, involved patients on enteric-coated mycophenolate sodium or those with multiorgan transplant, or provided no information on concomitant immunosuppressants. Data extracted were study design, sample size, immunosuppression regimen, type of transplant, and allograft outcomes. DATA SYNTHESIS Of 13 studies included, 1 was level I evidence, 3 were level II-2, 6 were level II-3, and 3 were level III evidence. Three focused on tacrolimus-based regimens, whereas 7 included either cyclosporine or tacrolimus. The only prospective, randomized, multicenter trial demonstrated that early taper of mycophenolate dosage to 1 g/day can be utilized without increased risk of rejection, compared with late tapering, but the rejection rate was high (30-40%). Overall, we found conflicting evidence regarding the impact of mycophenolate dose reduction on rejection rate and allograft loss and that discontinuing mycophenolate led to an increased risk of graft loss as high as 8 fold. Allograft survival was lowest in patients with gastrointestinal complications and those in whom mycophenolate was discontinued, compared with patients with neither gastrointestinal complications nor mycophenolate discontinuation. CONCLUSIONS Weak evidence suggests that mycophenolate dose modifications, either reduction or discontinuation, may increase rejection rate and graft loss; however, this is more apparent in cyclosporine-based regimens. Prospective, well-designed trials are necessary to definitively determine the impact of dose reduction in renal transplant recipients on tacrolimus-based regimens.
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Affiliation(s)
- Victoria Ch Su
- Victoria CH Su BSc (Pharm) ACPR, PharmD student, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Erica D Greanya
- Erica D Greanya BSc (Pharm) ACPR PharmD, Pharmacy Specialist-Solid Organ Transplantation, Vancouver General Hospital, Vancouver; Clinical Assistant Professor, Faculty of Pharmaceutical Sciences, The University of British Columbia
| | - Mary H H Ensom
- Mary HH Ensom BSc (Pharm) PharmD FASHP FCCP FCSHP FCAHS, Professor and Director, Doctor of Pharmacy Program, Faculty of Pharmaceutical Sciences, and Distinguished University Scholar, The University of British Columbia; Clinical Pharmacy Specialist, Children's and Women's Health Centre of British Columbia, Vancouver
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21
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Replacement of calcineurin inhibitors with everolimus: Long-term impact in renal transplant recipients – A single center study. INDIAN JOURNAL OF TRANSPLANTATION 2015. [DOI: 10.1016/j.ijt.2015.10.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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22
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Abstract
mTOR (mechanistic target of rapamycin) functions as the central regulator for cell proliferation, growth and survival. Up-regulation of proteins regulating mTOR, as well as its downstream targets, has been reported in various cancers. This has promoted the development of anti-cancer therapies targeting mTOR, namely fungal macrolide rapamycin, a naturally occurring mTOR inhibitor, and its analogues (rapalogues). One such rapalogue, everolimus, has been approved in the clinical treatment of renal and breast cancers. Although results have demonstrated that these mTOR inhibitors are effective in attenuating cell growth of cancer cells under in vitro and in vivo conditions, subsequent sporadic response to rapalogues therapy in clinical trials has promoted researchers to look further into the complex understanding of the dynamics of mTOR regulation in the tumour environment. Limitations of these rapalogues include the sensitivity of tumour subsets to mTOR inhibition. Additionally, it is well known that rapamycin and its rapalogues mediate their effects by inhibiting mTORC (mTOR complex) 1, with limited or no effect on mTORC2 activity. The present review summarizes the pre-clinical, clinical and recent discoveries, with emphasis on the cellular and molecular effects of everolimus in cancer therapy.
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23
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Baron D, Giral M, Brouard S. Reconsidering the detection of tolerance to individualize immunosuppression minimization and to improve long-term kidney graft outcomes. Transpl Int 2015; 28:938-59. [DOI: 10.1111/tri.12578] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Revised: 02/03/2015] [Accepted: 04/02/2015] [Indexed: 01/03/2023]
Affiliation(s)
- Daniel Baron
- INSERM; UMR 1064; Nantes France
- CHU de Nantes; ITUN; Nantes France
- Faculté de Médecine; Université de Nantes; Nantes France
| | - Magali Giral
- INSERM; UMR 1064; Nantes France
- CHU de Nantes; ITUN; Nantes France
- Faculté de Médecine; Université de Nantes; Nantes France
| | - Sophie Brouard
- INSERM; UMR 1064; Nantes France
- CHU de Nantes; ITUN; Nantes France
- Faculté de Médecine; Université de Nantes; Nantes France
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Rafii S, Roda D, Geuna E, Jimenez B, Rihawi K, Capelan M, Yap TA, Molife LR, Kaye SB, de Bono JS, Banerji U. Higher Risk of Infections with PI3K-AKT-mTOR Pathway Inhibitors in Patients with Advanced Solid Tumors on Phase I Clinical Trials. Clin Cancer Res 2015; 21:1869-76. [PMID: 25649020 PMCID: PMC4401558 DOI: 10.1158/1078-0432.ccr-14-2424] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2014] [Accepted: 01/28/2015] [Indexed: 01/20/2023]
Abstract
PURPOSE Novel antitumor therapies against the PI3K-AKT-mTOR pathway are increasingly used to treat cancer, either as single agents or in combination with chemotherapy or other targeted therapies. Although these agents are not known to be myelosuppressive, an increased risk of infection has been reported with rapamycin analogues. However, the risk of infection with new inhibitors of this pathway such as PI3K, AKT, mTORC 1/2, or multikinase inhibitors is unknown. EXPERIMENTAL DESIGN In this retrospective case-control study, we determined the incidence of infection in a group of 432 patients who were treated on 15 phase I clinical trials involving PI3K-AKT-mTOR pathway inhibitors (cases) versus a group of 100 patients on 10 phase I clinical trials of single agent non-PI3K-AKT-mTOR pathway inhibitors (controls) which did not involve conventional cytotoxic agents. We also collected data from 42 patients who were treated with phase I trials of combinations of PI3K-AKT-mTOR inhibitors and MEK inhibitors and 24 patients with combinations of PI3K-AKT-mTOR inhibitors and cytotoxic chemotherapies. RESULTS The incidence of all grade infection was significantly higher with all single-agent PI3K-AKT-mTOR inhibitors compared with the control group [27% vs. 8%, respectively, OR, 4.26; 95% confidence intervals (CI), 1.9-9.1, P = 0.0001]. The incidence of grade 3 and 4 infection was also significantly higher with PI3K-AKT-mTOR inhibitors compared with the control group (10.3% vs. 3%, OR, 3.74; 95% CI, 1.1-12.4; P = 0.02). Also, the combination of PI3K-AKT-mTOR inhibitors and chemotherapy was associated with a significantly higher incidence of all grade (OR, 4.79; 95% CI, 2.0-11.2; P = 0.0001) and high-grade (OR, 2.87; 95% CI, 1.0-7.6; P = 0.03) infection when compared with single-agent PI3K-AKT-mTOR inhibitors. CONCLUSIONS Inhibitors of the PI3K-AKT-mTOR pathway can be associated with a higher risk of infection. Combinations of PI3K-AKT-mTOR inhibitors and cytotoxic chemotherapy significantly increase the risk of infection. This should be taken into consideration during the design and conduct of trials involving PI3K-AKT-mTOR pathway inhibitors, particularly when combined with chemotherapy or myelosuppressive agents.
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Affiliation(s)
- Saeed Rafii
- Drug Development Unit, Division of Cancer Therapeutics and Division of Clinical Studies, The Institute of Cancer Research and The Royal Marsden, London, United Kingdom
| | - Desamparados Roda
- Drug Development Unit, Division of Cancer Therapeutics and Division of Clinical Studies, The Institute of Cancer Research and The Royal Marsden, London, United Kingdom
| | - Elena Geuna
- Drug Development Unit, Division of Cancer Therapeutics and Division of Clinical Studies, The Institute of Cancer Research and The Royal Marsden, London, United Kingdom
| | - Begona Jimenez
- Drug Development Unit, Division of Cancer Therapeutics and Division of Clinical Studies, The Institute of Cancer Research and The Royal Marsden, London, United Kingdom
| | - Karim Rihawi
- Drug Development Unit, Division of Cancer Therapeutics and Division of Clinical Studies, The Institute of Cancer Research and The Royal Marsden, London, United Kingdom
| | - Marta Capelan
- Drug Development Unit, Division of Cancer Therapeutics and Division of Clinical Studies, The Institute of Cancer Research and The Royal Marsden, London, United Kingdom
| | - Timothy A Yap
- Drug Development Unit, Division of Cancer Therapeutics and Division of Clinical Studies, The Institute of Cancer Research and The Royal Marsden, London, United Kingdom
| | - L Rhoda Molife
- Drug Development Unit, Division of Cancer Therapeutics and Division of Clinical Studies, The Institute of Cancer Research and The Royal Marsden, London, United Kingdom
| | - Stanley B Kaye
- Drug Development Unit, Division of Cancer Therapeutics and Division of Clinical Studies, The Institute of Cancer Research and The Royal Marsden, London, United Kingdom
| | - Johann S de Bono
- Drug Development Unit, Division of Cancer Therapeutics and Division of Clinical Studies, The Institute of Cancer Research and The Royal Marsden, London, United Kingdom
| | - Udai Banerji
- Drug Development Unit, Division of Cancer Therapeutics and Division of Clinical Studies, The Institute of Cancer Research and The Royal Marsden, London, United Kingdom.
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Vardhan H, Prasad N, Jaiswal A, Yadav B, Kumar S, Bhadauria D, Kaul A, Gupta A, Srivartava A, Sharma RK. Outcomes of living donor renal transplant recipients with and without basiliximab induction: A long-term follow-up study. INDIAN JOURNAL OF TRANSPLANTATION 2014. [DOI: 10.1016/j.ijt.2014.06.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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Kimura Y, Fujimura C, Ito Y, Takahashi T, Aiba S. Evaluation of the Multi-ImmunoTox Assay composed of 3 human cytokine reporter cells by examining immunological effects of drugs. Toxicol In Vitro 2014; 28:759-68. [PMID: 24603311 DOI: 10.1016/j.tiv.2014.02.013] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Revised: 01/30/2014] [Accepted: 02/24/2014] [Indexed: 11/16/2022]
Abstract
We established a luciferase reporter assay system, the Multi-ImmunoTox Assay (MITA), to evaluate the effects on key predictivein vitro components of the human immune system. The system is composed of 3 stable reporter cell lines transfected with 3 luciferase genes, SLG, SLO, and SLR, under the control of 4 cytokine promoters, IL-2, IFN-γ, IL-1β, and IL-8, and the G3PDH promoter. We first compared the effects of dexamethasone, cyclosporine, and tacrolimus on these cell lines stimulated with phorbol 12-myristate 13-acetate and ionomycin, or lipopolysaccharides, with those on mRNA expression by the mother cell lines and human whole blood cells after stimulation. The results demonstrated that MITA correctly reflected the change of mRNA of the mother cell lines and whole blood cells. Next, we evaluated other immunosuppressive drugs, off-label immunosuppressive drugs, and non-immunomodulatory drugs. Although MITA did not detect immunosuppressive effects of either alkylating agents or antimetabolites, it could demonstrate those of the off-label immunosuppressive drugs, sulfasalazine, chloroquine, minocycline, and nicotinamide. Compared with the published immunological effects of the drugs, these data suggest that MITA can present a novel high-throughput approach to detect immunological effects of chemicals other than those that induce immunosuppressive effects through their inhibitory action on cell division.
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Affiliation(s)
- Yutaka Kimura
- Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
| | - Chizu Fujimura
- Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
| | - Yumiko Ito
- Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
| | - Toshiya Takahashi
- Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
| | - Setsuya Aiba
- Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.
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Zaza G, Tomei P, Granata S, Boschiero L, Lupo A. Monoclonal antibody therapy and renal transplantation: focus on adverse effects. Toxins (Basel) 2014; 6:869-91. [PMID: 24590384 PMCID: PMC3968366 DOI: 10.3390/toxins6030869] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2013] [Revised: 02/07/2014] [Accepted: 02/21/2014] [Indexed: 02/06/2023] Open
Abstract
A series of monoclonal antibodies (mAbs) are commonly utilized in renal transplantation as induction therapy (a period of intense immunosuppression immediately before and following the implant of the allograft), to treat steroid-resistant acute rejections, to decrease the incidence and mitigate effects of delayed graft function, and to allow immunosuppressive minimization. Additionally, in the last few years, their use has been proposed for the treatment of chronic antibody-mediated rejection, a major cause of late renal allograft loss. Although the exact mechanism of immunosuppression and allograft tolerance with any of the currently used induction agents is not completely defined, the majority of these medications are targeted against specific CD proteins on the T or B cells surface (e.g., CD3, CD25, CD52). Moreover, some of them have different mechanisms of action. In particular, eculizumab, interrupting the complement pathway, is a new promising treatment tool for acute graft complications and for post-transplant hemolytic uremic syndrome. While it is clear their utility in renal transplantation, it is also unquestionable that by using these highly potent immunosuppressive agents, the body loses much of its innate ability to mount an adequate immune response, thereby increasing the risk of severe adverse effects (e.g., infections, malignancies, haematological complications). Therefore, it is extremely important for clinicians involved in renal transplantation to know the potential side effects of monoclonal antibodies in order to plan a correct therapeutic strategy minimizing/avoiding the onset and development of severe clinical complications.
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Affiliation(s)
- Gianluigi Zaza
- Renal Unit, Department of Medicine, University-Hospital of Verona, Piazzale A. Stefani 1, Verona 37126, Italy.
| | - Paola Tomei
- Renal Unit, Department of Medicine, University-Hospital of Verona, Piazzale A. Stefani 1, Verona 37126, Italy.
| | - Simona Granata
- Renal Unit, Department of Medicine, University-Hospital of Verona, Piazzale A. Stefani 1, Verona 37126, Italy.
| | - Luigino Boschiero
- First Surgical Clinic, Kidney Transplantation Center, University-Hospital of Verona, Piazzale A. Stefani 1, Verona 37126, Italy.
| | - Antonio Lupo
- Renal Unit, Department of Medicine, University-Hospital of Verona, Piazzale A. Stefani 1, Verona 37126, Italy.
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Everolimus monotherapy or combined therapy in liver transplantation: indications and results. Transplant Proc 2014; 45:1971-4. [PMID: 23769086 DOI: 10.1016/j.transproceed.2013.01.075] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2012] [Accepted: 01/24/2013] [Indexed: 01/11/2023]
Abstract
INTRODUCTION Everolimus is a potent immunosuppressant with several advantages over calcineurin inhibitors, such as good tolerance, preventive effects on cardiovascular morbidity, and mortality and cancer prevention as it inhibits cell proliferation. PATIENTS AND METHODS Between April 1986 and December 2010, we performed 1500 liver transplants (OLT) in 1341 recipients, including 57 patients who were prescribed everolimus 24 (42.1%) as monotherapy and 33 (57.9%) as treatments combined with other immunosuppressants. We performed a retrospective analysis of our experience with conversion to everolimus in OLT recipients. RESULTS The 43 men and 14 women had a mean overall age at transplantation of 59.1 ± 10 years. The most frequent indication for OLT was hepatocellular carcinoma (HCC; 53.8%). Everolimus was introduced to prevent HCC recurrence (53%), development of de novo tumors (33%), address renal dysfunction (7%), or overcome side effects of other immunosuppressants (7%). We observed a significant improvement in renal function using the estimated glomerular filtration rate (Crockcroft-Gault formula) from 68.5 mL/min before to 74.5 mL/min after switching to everolimus. The 72% of recipients who developed ≥1 adverse event, most frequently showed hyperlipidemia (34.4%). CONCLUSION Both monotherapy and combined everolimus regimens were well-tolerated immunosuppressive regimens in liver transplant recipients with recurrent or de novo malignancies. Everolimus improved renal function. The most common side effects were hyperlipidemia, edema, and mouth ulcerations, which were well controlled with anti-lipidemic agents or decreased everolimus dosages.
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Lee RA, Gabardi S. Current trends in immunosuppressive therapies for renal transplant recipients. Am J Health Syst Pharm 2013; 69:1961-75. [PMID: 23135563 DOI: 10.2146/ajhp110624] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
PURPOSE Current trends in immunosuppressive therapies for renal transplant recipients are reviewed. SUMMARY The common premise for immunosuppressive therapies in renal transplantation is to use multiple agents to work on different immunologic targets. The use of a multidrug regimen allows for pharmacologic activity at several key steps in the T-cell replication process and lower dosages of each individual agent, thereby producing fewer drug-related toxicities. In general, there are three stages of clinical immunosuppression: induction therapy, maintenance therapy, and treatment of an established acute rejection episode. Only immunosuppressive therapies used for maintenance therapy are discussed in detail in this review. The most common maintenance immunosuppressive agents can be divided into five classes: (1) the calcineurin inhibitors (CNIs) (cyclosporine and tacrolimus), (2) costimulation blockers (belatacept), (3) mammalian target of rapamycin inhibitors (sirolimus and everolimus), (4) antiproliferatives (azathioprine and mycophenolic acid derivatives), and (5) corticosteroids. Immunosuppressive regimens vary among transplantation centers but most often include a CNI and an adjuvant agent, with or without corticosteroids. Selection of appropriate immunosuppressive regimens should be patient specific, taking into account the medications' pharmacologic properties, adverse-event profile, and potential drug-drug interactions, as well as the patient's preexisting diseases, risk of rejection, and medication regimen. CONCLUSION Advancements in transplant immunosuppression have resulted in a significant reduction in acute cellular rejection and a modest increase in long-term patient and graft survival. Because the optimal immunosuppression regimen is still unknown, immunosuppressant use should be influenced by institutional preference and tailored to the immunologic risk of the patient and adverse-effect profile of the drug.
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Affiliation(s)
- Ruth-Ann Lee
- Department of Pharmacy, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7574, USA.
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Donor-Derived Mesenchymal Stem Cells Combined With Low-Dose Tacrolimus Prevent Acute Rejection After Renal Transplantation. Transplantation 2013; 95:161-8. [DOI: 10.1097/tp.0b013e3182754c53] [Citation(s) in RCA: 138] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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Chouhan KK, Zhang R. Antibody induction therapy in adult kidney transplantation: A controversy continues. World J Transplant 2012; 2:19-26. [PMID: 24175192 PMCID: PMC3782231 DOI: 10.5500/wjt.v2.i2.19] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2011] [Revised: 03/14/2012] [Accepted: 03/20/2012] [Indexed: 02/05/2023] Open
Abstract
Antibody induction therapy is frequently used as an adjunct to the maintenance immunosuppression in adult kidney transplant recipients. Published data support antibody induction in patients with immunologic risk to reduce the incidence of acute rejection (AR) and graft loss from rejection. However, the choice of antibody remains controversial as the clinical studies were carried out on patients of different immunologic risk and in the context of varying maintenance regimens. Antibody selection should be guided by a comprehensive assessment of immunologic risk, patient comorbidities, financial burden as well as the maintenance immunosuppressives. Lymphocyte-depleting antibody (thymoglobulin, ATGAM or alemtuzumab) is usually recommended for those with high risk of rejection, although it increases the risk of infection and malignancy. For low risk patients, interleukin-2 receptor antibody (basiliximab or daclizumab) reduces the incidence of AR without much adverse effects, making its balance favorable in most patients. It should also be used in the high risk patients with other medical comorbidities that preclude usage of lymphocyte-depleting antibody safely. There are many patients with very low risk, who may be induced with intravenous steroids without any antibody, as long as combined potent immunosuppressives are kept as maintenance. In these patients, benefits with antibody induction may be too small to outweigh its adverse effects and financial cost. Rituximab can be used in desensitization protocols for ABO and/or HLA incompatible transplants. There are emerging data suggesting that alemtuzumab induction be more successful than other antibody for promoting less intensive maintenance protocols, such as steroid withdrawal, tacrolimus monotherapy or lower doses of tacrolimus and mycophenolic acid. However, the long-term efficacy and safety of these unconventional strategies remains unknown.
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Affiliation(s)
- Kanwaljit K Chouhan
- Kanwaljit K Chouhan, Rubin Zhang, Section of Nephrology, Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, United States
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Wilson CGM, Arkin MR. Small-molecule inhibitors of IL-2/IL-2R: lessons learned and applied. Curr Top Microbiol Immunol 2011; 348:25-59. [PMID: 20703966 DOI: 10.1007/82_2010_93] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/17/2023]
Abstract
The IL-2:IL-2R protein-protein interaction is of central importance to both healthy and diseased immune responses, and is one of the earliest examples of successful small-molecule inhibitor discovery against this target class. Drug-like inhibitors of IL-2 have been identified through a combination of fragment discovery, structure-based design, and medicinal chemistry; this discovery approach illustrates the importance of using a diverse range of complementary screening methods and analytical tools to achieve a comprehensive understanding of molecular recognition. The IL-2 story also provides insight into the dynamic nature of protein-protein interaction surfaces, their potential druggability, and the physical and chemical properties of effective small-molecule ligands. These lessons, from IL-2 and similar discovery programs, underscore an increasing awareness of the principles governing the development of drugs for protein-protein interactions.
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Affiliation(s)
- C G M Wilson
- Small Molecule Discovery Center, University of California, San Francisco, CA 94158, USA
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Gabardi S, Martin ST, Roberts KL, Grafals M. Induction immunosuppressive therapies in renal transplantation. Am J Health Syst Pharm 2011; 68:211-8. [PMID: 21258026 DOI: 10.2146/ajhp090636] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
PURPOSE Induction immunosuppressive therapies for patients undergoing renal transplantation are reviewed. SUMMARY The goal of induction therapy is to prevent acute rejection during the early posttransplantation period by providing a high degree of immunosuppression at the time of transplantation. Induction therapy is often considered essential to optimize outcomes, particularly in patients at high risk for poor short-term outcomes. All of the induction immunosuppressive agents currently used are biological agents and are either monoclonal (muromonab-CD3, daclizumab, basiliximab, alemtuzumab) or polyclonal (antithymocyte globulin [equine] or antithymocyte globulin [rabbit]) antibodies. Although antithymocyte globulin (rabbit) is not labeled for induction therapy, it is used for this purpose more than any other agent. Basiliximab is not considered as potent an immunosuppressive agent but has a much more favorable adverse-effect profile compared with antithymocyte globulin (rabbit) and is most commonly used in patients at low risk for acute rejection. Rituximab is being studied for use as induction therapy but to date has not demonstrated any significant benefits over placebo. While head-to-head data are available comparing most induction agents, the final decision on the most appropriate induction therapy for a transplant recipient is highly dependent on preexisting medical conditions, donor characteristics, and the maintenance immunosuppressive regimen to be used. CONCLUSION No standard induction immunosuppressive regimen exists for patients undergoing renal transplantation. Antithymocyte globulin (rabbit) is the most commonly used agent, whereas basiliximab appears safer. The choice of regimen depends on the preferences of clinicians and institutions.
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Affiliation(s)
- Steven Gabardi
- Department of Transplant Surgery, Brigham and Women’s Hospital, Boston, MA 02115, USA.
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Abstract
Therapeutic drug monitoring is a well-established approach in transplantation medicine to guide immunosuppressive therapy. However, it cannot always predict the effects of immunosuppressive drugs on immune cells, because it does not reflect any aspect of an individual patient's immune system. Pharmacodynamic monitoring is a more recent strategy to provide information about the biologic effect of a specific drug or drug combination on the individual transplant patient. Currently, there is a large number of different biomarkers that either directly (specific markers) or indirectly (global markers) relate to the pharmacodynamic effects of immunosuppressive drugs and are under investigation as potential candidates to be introduced in clinical practice. Such biomarkers may be useful to identify patients at risk of developing acute rejection, infection, or cancer as well as patients who are suitable for minimization of immunosuppressant therapy and may be helpful to manage the timing and rate of immunosuppressant weaning. Serial longitudinal monitoring may allow maintenance of an individualized immunosuppressive regimen. Thus, biomarker monitoring is a potential complementary tool to therapeutic drug monitoring. This review summarizes the current state of knowledge about the use of a number of global or drug-specific pharmacodynamic biomarkers. It is not a comprehensive overview of the literature available, but rather an evidence-based reflection by experts who are intensively involved in scientific work in this field.
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Abstract
This article provides an overview of the ethical issues associated with penile transplantation, a form of composite tissue allografting. There is only one reported case of human penile transplantation, and, as such, this technique is considered to be experimental. The ethical issues at stake involve both the graft donor and the graft recipient. With regard to the recipient, there are significant concerns relating to surgical risks and benefits, informed consent, body image (including surgical expectations and outcomes) and compliance. Donor issues may include family consent and privacy, as well as graft harvesting (leaving the donor cadaver without a penis). Many of these ethical issues can be explored during the recipient's assessment and consent process. Because no medium-term or long-term outcome data for this procedure exist-only one such operation has ever been performed-the burdens and ethical issues concerning penile transplantation remain unknown.
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Affiliation(s)
- Li-Chao Zhang
- Department of Urology, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou 510010, China
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Dalal P, Shah G, Chhabra D, Gallon L. Role of tacrolimus combination therapy with mycophenolate mofetil in the prevention of organ rejection in kidney transplant patients. Int J Nephrol Renovasc Dis 2010; 3:107-15. [PMID: 21694936 PMCID: PMC3108777 DOI: 10.2147/ijnrd.s7044] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2010] [Indexed: 01/28/2023] Open
Abstract
Introduction: Several new medications are now available for immunosuppression in the kidney transplant field. Tacrolimus and mycophenolate mofetil were first introduced for immunosuppression in renal transplantation in the mid 1990s. Since then, the combination of tacrolimus and mycophenolate mofetil has been evaluated in numerous clinical trials. The outcomes of these trials have varied due to differences in induction and/or maintenance therapy, drug dosing and monitoring protocols, and study design. The aim of this review is to analyze the literature critically and to provide an overview of tacrolimus and mycophenolate mofetil combination therapy in renal transplantation.
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Affiliation(s)
- P Dalal
- Department of Medicine, Mount Sinai Hospital, Chicago, Illinois, USA
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Sollinger HW. Enteric-coated mycophenolate sodium - current and future use in transplant patients. Expert Rev Clin Immunol 2010; 1:203-11. [PMID: 20476934 DOI: 10.1586/1744666x.1.2.203] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Mycophenolate mofetil, the morpholino ester prodrug of mycophenolic acid, is an effective immunosuppressant, although there are concerns over dose reductions and discontinuations due to gastrointestinal adverse events. Enteric-coated mycophenolate sodium (Myfortic) was formulated to improve mycophenolic acid-related upper gastrointestinal adverse events and to deliver effective mycophenolic acid protection. Enteric-coated mycophenolate sodium 720 mg and mycophenolate mofetil 1000 mg are therapeutically equivalent in de novo transplant patients. Conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in maintenance patients can be achieved without compromising safety and efficacy. Recent studies demonstrate the efficacy and tolerability of enteric-coated mycophenolate sodium in adult and pediatric renal transplant patients converted from mycophenolate mofetil, and early results also suggest that enteric-coated mycophenolate sodium can provide similar efficacy and safety as mycophenolate mofetil in de novo heart transplant patients.
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Affiliation(s)
- Hans W Sollinger
- University of Wisconsin School of Medicine, Department of Surgery, 600 Highland Avenue, Madison, WI 53792, USA.
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De Novo Everolimus-Based Therapy in Renal Transplant Recipients: Effect on Proteinuria and Renal Prognosis. Transplant Proc 2010; 42:1297-302. [DOI: 10.1016/j.transproceed.2010.03.120] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Gheysens O, Lin S, Cao F, Wang D, Chen IY, Rodriguez-Porcel M, Min JJ, Gambhir SS, Wu JC. Noninvasive evaluation of immunosuppressive drug efficacy on acute donor cell survival. Mol Imaging Biol 2009; 8:163-70. [PMID: 16555032 PMCID: PMC4161130 DOI: 10.1007/s11307-006-0038-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
PURPOSE The therapeutic benefits of cell transplantation may depend on the survival of sufficient numbers of grafted cells. We evaluate four potent immunosuppressive medications aimed at preventing acute donor cell death. PROCEDURES AND RESULTS Embryonic rat H9c2 myoblasts were stably transduced to express firefly luciferase reporter gene (H9c2-Fluc). H9c2-Fluc cells (3x10(6)) were injected into thigh muscles of Sprague-Dawley rats (N=30) treated with cyclosporine, dexamethasone, mycophenolate mofetil, tacrolimus, or saline from day -3 to day +14. Longitudinal optical bioluminescence imaging was performed over two weeks. Fluc activity was 40.0+/-12.1% (dexamethasone), 30.5+/-12.5% (tacrolimus), and 21.5+/-3.5% (mycophenolate) vs. 12.0+/-5.0% (control) and 8.3+/-5.0% (cyclosporine) at day 4 (P<0.05). However, by day 14, cell signals had decreased drastically to <10% for all groups despite drug therapy. CONCLUSION This study demonstrates the ability of optical molecular imaging for tracking cell survival noninvasively and raises important questions with regard to the overall efficacy of immunosuppressives for prolonging transplanted cell survival.
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Affiliation(s)
- Olivier Gheysens
- Department of Radiology and Bio-X Program, Stanford University, Palo Alto, CA, USA
| | - Shuan Lin
- Department of Radiology and Bio-X Program, Stanford University, Palo Alto, CA, USA
| | - Feng Cao
- Department of Radiology and Bio-X Program, Stanford University, Palo Alto, CA, USA
| | - Dongxu Wang
- Department of Radiology and Bio-X Program, Stanford University, Palo Alto, CA, USA
| | - Ian Y. Chen
- Department of Radiology and Bio-X Program, Stanford University, Palo Alto, CA, USA
| | | | - Jung J. Min
- Department of Radiology and Bio-X Program, Stanford University, Palo Alto, CA, USA
| | - Sanjiv S. Gambhir
- Department of Radiology and Bio-X Program, Stanford University, Palo Alto, CA, USA
- Department of Bioengineering, Stanford University, Palo Alto, CA, USA
| | - Joseph C. Wu
- Department of Radiology and Bio-X Program, Stanford University, Palo Alto, CA, USA
- Department of Medicine, Division of Cardiology, Stanford University, Palo Alto, CA, USA
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Lücke T, Kanzelmeyer N, Baradaran-Heravi A, Boerkoel CF, Burg M, Ehrich JHH, Pape L. Improved outcome with immunosuppressive monotherapy after renal transplantation in Schimke-immuno-osseous dysplasia. Pediatr Transplant 2009; 13:482-9. [PMID: 18785907 DOI: 10.1111/j.1399-3046.2008.01013.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
SIOD is a multisystem disorder caused by a mutant chromatin remodelling protein. The main clinical findings are spondyloepiphyseal dysplasia with disproportionate growth restriction, defective cellular immunity, and steroid-resistant nephrotic syndrome secondary to biopsy proven FSGS leading to ESRF. Concerning ESRF, kidney transplantation is the therapy of choice since FSGS does not recur in the graft. However, with respect to the underlying immune disorder and the increased susceptibility to life threatening infections, the question of the optimal immunosuppressive therapy after renal transplantation remains unresolved. Under conventional immunosuppressive regimens some SIOD patients have developed severe disseminated cutaneous papilloma virus infections or EBV associated lymphoproliferative disease. We present several cases of children with SIOD (four of five had SMARCAL1 mutations) and monotherapy maintenance immunosuppression after renal transplantation and compare them with 13 patients from the SIOD registry. We have found that post-renal transplantation immunosuppressive monotherapy results in a good outcome with a reduced number of severe infections. Due to the underlying immunodeficiency in SIOD, limited immunosuppression may be possible without increasing the risk of acute or chronic rejection.
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Affiliation(s)
- Thomas Lücke
- Department of Pediatric Nephrology, Hannover Medical School, Hannover, Germany.
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Abstract
Although calcineurin inhibitors (CNIs) are effective at preventing acute rejection, their long-term use is associated with nephrotoxicity that may compromise long-term renal allograft survival. Consequently, there is considerable interest in identifying immunosuppressive regimens that permit reduced exposure to CNIs while maintaining adequate immunosuppression. Introducing such strategies early after transplantation may mean that the development of CNI-associated nephrotoxicity could be minimized or prevented. Several CNI-sparing regimens have shown at least comparable efficacy with standard-dose CNI regimens. In particular, a regimen of mycophenolate mofetil (MMF), corticosteroids, interleukin-2 receptor antagonist induction, and low-dose tacrolimus from the time of transplantation provided superior renal function and a lower acute rejection rate than the same regimen but with low-dose cyclosporine or low-dose sirolimus, or standard-dose cyclosporine, MMF, and corticosteroids. The use of low-dose cyclosporine does not seem to eliminate nephrotoxicity in de novo renal transplant recipients. The early withdrawal of CNIs from MMF-based regimens generally improves renal function but has been associated with an increased risk of acute rejection, in particular when the levels of mycophenolic acid were not adjusted to maintain the same total level of immunosuppression. Research aiming to achieve the "best" balance of efficacy and toxicity of available immunosuppressive regimens continues.
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Maintenance immunosuppressive therapy in adult renal transplantation: A single center analysis. Transpl Immunol 2008; 20:14-20. [DOI: 10.1016/j.trim.2008.08.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2008] [Accepted: 08/07/2008] [Indexed: 11/18/2022]
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Colantonio DA, Borden KK, Clarke W. Comparison of the CEDIA® and MEIA® assays for the measurement of sirolimus in organ transplant recipients. Clin Biochem 2007; 40:680-7. [PMID: 17428457 DOI: 10.1016/j.clinbiochem.2007.02.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2006] [Revised: 01/25/2007] [Accepted: 02/11/2007] [Indexed: 11/18/2022]
Abstract
OBJECTIVES This study evaluated two immunoassays, the CEDIA assay and the MEIA assay, used for the measurement of whole blood levels of sirolimus in organ transplant recipients. DESIGN AND METHODS We report on the performance characteristics (total precision, limit of quantitation (functional sensitivity), limit of detection (analytical sensitivity), linearity, accuracy) for each assay. Patient correlation studies were performed, and the results were analyzed using Bland-Altman plots and Passing-Bablok analysis. RESULTS Total precision for the MEIA assay, corresponding to three mean concentrations of 5.0, 10.6 and 20.2 ng/mL, was 10.5, 8.5, and 6.7%, respectively. The limit of detection was determined to be 1.1 ng/mL and the limit of quantitation was 1.5 ng/mL. The mean recovery for CEDIA was 105.4%, and analysis of proficiency material demonstrated a large negative bias with respect to the mass spectrometry peer mean-later determined to be due to matrix interference. Results for the CEDIA assay showed a total precision, corresponding to a mean concentration of 5.4, 10.5 and 20.7 ng/mL, of 13.5, 5.6, and 4.1%, respectively. The limit of detection was found to be 4.8 ng/mL, with a limit of quantitation of 5.2 ng/mL. The mean recovery for MEIA was 110.1%, and analysis of proficiency material demonstrated good agreement with the mass spectrometry peer mean with a slight positive bias. Both assays were acceptably linear over the reportable range of the assay. Patient correlation studies demonstrated a positive average bias for both assays versus results from LC-MS measurement (0.9 ng/mL for MEIA, 2.1 ng/mL for CEDIA). CONCLUSION Based on this evaluation, the MEIA demonstrated acceptable performance for use in clinical monitoring of sirolimus. However, based on a higher limit of quantitation that falls within the therapeutic interval, the CEDIA is not recommended for clinical monitoring of sirolimus.
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Affiliation(s)
- David A Colantonio
- Johns Hopkins University School of Medicine, Baltimore, MD 21287-7065, USA
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Samaniego M, Becker BN, Djamali A. Drug Insight: maintenance immunosuppression in kidney transplant recipients. ACTA ACUST UNITED AC 2006; 2:688-99. [PMID: 17124526 DOI: 10.1038/ncpneph0343] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2006] [Accepted: 09/11/2006] [Indexed: 12/31/2022]
Abstract
Kidney transplantation is the treatment of choice for patients with end-stage renal disease, in part because of ongoing efforts towards improving immunosuppressive strategies. Although calcineurin inhibitors remain the mainstay of immunosuppression in kidney transplant recipients, within this class of drug there has been a shift from use of ciclosporin to use of tacrolimus. Mycophenolate mofetil and mycophenolate sodium are now the antimetabolites of choice. A new class of drugs (inhibitors of mammalian target of rapamycin) that includes sirolimus is being increasingly used in stable kidney transplant recipients. New data, however, indicate that a more cautious approach to the use of this drug is warranted. Many transplant centers are now using steroid avoidance, minimization and withdrawal protocols. The impact of these different drugs and therapeutic strategies on outcomes has to be weighed against their immunosuppressive benefit. As more and more community-based nephrologists and primary care physicians are becoming involved in the care of stable kidney transplant recipients, it is important for these clinicians to familiarize themselves with novel immunosuppressive drugs and their pharmacokinetic properties.
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Affiliation(s)
- Millie Samaniego
- Nephrology Section, Department of Medicine, University of Wisconsin Madison, 3034 Fish Hatchery Road, Suite B, Madison, WI 53713, USA
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Altomare JF, Smith RE, Potdar S, Mitchell SH. Delayed Gastric Ulcer Healing Associated with Sirolimus. Transplantation 2006; 82:437-8. [PMID: 16906046 DOI: 10.1097/01.tp.0000228900.24951.66] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Abstract
High throughput, high density platforms for transcriptional, proteomic, and metabonomic analyses are opening new doors for improving our understanding of the complexity and redundancy of the immune system in the interplay of the innate and allo-immune responses in organ transplantation. New insights are being obtained into the possible discrepancies between the gold standard of tissue pathological diagnosis and clinical graft outcomes, as new transcriptional categories of transplant rejection evolve. The bystander effects of chronic immunosuppression underlying the complexities of graft dysfunction are beginning to be understood. Non-invasive mechanisms to monitor transplants, by following 'footprints' of biomarker sets that reflect the disease phenotype, are being pursued for their clinical application for direct patient care. Utilization of these same biomarker sets may also offer a unique means to titrate immunosuppression and predict specific graft dysfunction events prior to clinical decline, thus bringing in the potential to reduce patient morbidity from infection and malignancy, preserve graft integrity, and limit the progression of chronic graft injury. Bioinformatics support is integral to the unraveling of the mysteries of the human genome, proteome, and metabolome in disease and in health.
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Affiliation(s)
- Minnie M Sarwal
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94304, USA.
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