|
1
|
Butuca A, Stoicescu L, Popa ML, Dobrea CM, Muntean A, Morgovan C, Pienar C, Gligor FG, Ghibu S, Popa Ilie IR, Frum A. Inefficiency Rates of Biological Immunosuppressive Induction Agents Used in Organ Transplantation: A Pharmacovigilance Study. J Clin Med 2025; 14:3409. [PMID: 40429403 PMCID: PMC12112635 DOI: 10.3390/jcm14103409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2025] [Revised: 04/27/2025] [Accepted: 04/30/2025] [Indexed: 05/29/2025] Open
Abstract
Effective immunosuppressant pharmacotherapy is essential for successful organ transplantation. Background/Objectives: Generally, induction therapy includes basiliximab (BAS) or anti-thymocyte globulin (THY). However, other biological molecules have been used to accelerate firm immunosuppression. A reduced effectiveness of these induction agents increases the risk of graft rejection. This study aims to evaluate the ineffectiveness rate of biological molecules based on spontaneous reports uploaded to the EudraVigilance database. Methods: Specific topics related to the safety profiles of alemtuzumab, BAS, belatacept, and THY were analyzed. A total of 23 preferred terms describing drug resistance, drug ineffectiveness, and transplant rejection were used as the inclusion criteria. Descriptive and disproportionality analyses were performed. Results: Regarding the four molecules, 18,564 safety reports were communicated, with n = 5089 (27.4%) for THY and n = 3469 (18.7%) for BAS. Most adverse drug reactions (ADRs) for THY, BAS, and belatacept affected the adult male population. As expected, the majority of the ADRs were linked to infections, followed by general disorders. BAS presented higher probabilities of drug resistance and transplant rejection being reported among the four molecules. A higher probability of reporting drug ineffectiveness was noted for THY than for the other molecules. Conclusions: All the molecules showed small frequencies regarding resistance. As expected, transplant rejection was more frequently reported for all molecules (especially for BAS), accompanied by a notable variability in reporting frequencies. However, a causal relationship between the reported adverse reactions and drug efficacy cannot be established based on the present results. Further real-world evidence studies will enhance our understanding of the safety and efficacy of these drugs in transplant patients.
Collapse
Affiliation(s)
- Anca Butuca
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (A.B.); (C.M.); (F.G.G.); (A.F.)
| | - Laurentiu Stoicescu
- Internal Medicine Department, Faculty of Medicine, “Iuliu Haţieganu” University of Medicine and Pharmacy, 400000 Cluj-Napoca, Romania;
- Cardiology Department, Clinical Municipal Hospital, 400139 Cluj-Napoca, Romania
| | - Mirela Livia Popa
- Clinic Medical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania
| | - Carmen Maximiliana Dobrea
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (A.B.); (C.M.); (F.G.G.); (A.F.)
| | - Adriana Muntean
- Clinical Institute of Urology and Renal Transplant Cluj-Napoca, 4-6 Clinicilor Str., 400006 Cluj-Napoca, Romania;
| | - Claudiu Morgovan
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (A.B.); (C.M.); (F.G.G.); (A.F.)
| | - Corina Pienar
- Department of Pediatrics, 2nd Pediatrics Clinic, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania;
| | - Felicia Gabriela Gligor
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (A.B.); (C.M.); (F.G.G.); (A.F.)
| | - Steliana Ghibu
- Department of Pharmacology, Physiology and Pathophysiology, Faculty of Pharmacy, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
| | - Ioana Rada Popa Ilie
- Department of Endocrinology, Faculty of Medicine, “Iuliu Haţieganu” University of Medicine and Pharmacy, 3-5 Louis Pasteur Street, 400349 Cluj-Napoca, Romania;
| | - Adina Frum
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (A.B.); (C.M.); (F.G.G.); (A.F.)
| |
Collapse
|
|
2
|
Katalinić N, Crnić Marčetić T, Trobonjača Z, Barin-Turica F, Balen S. Development of the Crossmatch Test in Kidney Transplantation Up to the Virtual Level. J Clin Med 2025; 14:1288. [PMID: 40004818 PMCID: PMC11856696 DOI: 10.3390/jcm14041288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 02/12/2025] [Accepted: 02/14/2025] [Indexed: 02/27/2025] Open
Abstract
The Human Leukocyte Antigen (HLA) system forms the central part of the immune system and is crucial in the recognition and elimination of "non-self" antigens. While this role of the HLA system is essential in the effective defense of the organism against pathogens, it is undesirable in organ and tissue transplantation because it enables the recognition of mismatched HLA molecules of the donor as being foreign and stimulates the graft rejection reaction. Organ transplantation involves the introduction of antigens that are more or less mismatched to the recipient; therefore, in order to achieve the best possible match in the HLA system between the recipient and the donor, a whole series of immunogenetic tests is performed, including crossmatching (XM). If performed before kidney transplantation, it represents the final in vitro test to rule out the presence of donor-specific antibodies, which may cause graft rejection and which may not have been detected by earlier serum screening. The beginning of XM was marked by the complement-dependent cytotoxicity (CDC) method developed by Terasaki and colleagues in 1964. Later, as a result of advances in technology and the need for methods that overcome the limitations of CDC, flow cytometry and Luminex XM assays were developed. The introduction of solid-phase technology brought a new dimension to the detection of low-level HLA antibodies and the determination of their specificities, which enabled the development and implementation of the virtual XM test (vXM). It is an in silico test that assesses the immunological match between the recipient and the organ donor based on the analysis of the specificity of the antibodies present in the recipient's serum and the HLA typing of the organ donor. Each method has its own advantages and limitations, which are described below and need to be taken into account, considering their significant impact on clinical application in kidney transplantation.
Collapse
Affiliation(s)
- Nataša Katalinić
- Tissue Typing Laboratory, Clinical Institute for Transfusion Medicine, Clinical Hospital Center Rijeka, 51000 Rijeka, Croatia; (T.C.M.); (S.B.)
- Department of Clinical Laboratory Diagnostics, Faculty of Medicine in Rijeka, University of Rijeka, 51000 Rijeka, Croatia
| | - Tajana Crnić Marčetić
- Tissue Typing Laboratory, Clinical Institute for Transfusion Medicine, Clinical Hospital Center Rijeka, 51000 Rijeka, Croatia; (T.C.M.); (S.B.)
| | - Zlatko Trobonjača
- Department of Physiology, Immunology and Pathophysiology, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia;
| | | | - Sanja Balen
- Tissue Typing Laboratory, Clinical Institute for Transfusion Medicine, Clinical Hospital Center Rijeka, 51000 Rijeka, Croatia; (T.C.M.); (S.B.)
- Department of Clinical Laboratory Diagnostics, Faculty of Medicine in Rijeka, University of Rijeka, 51000 Rijeka, Croatia
| |
Collapse
|
|
3
|
Das R, Greenspan NS. Understanding HLA-DQ in renal transplantation: a mini-review. Front Immunol 2025; 16:1525306. [PMID: 39975547 PMCID: PMC11835797 DOI: 10.3389/fimmu.2025.1525306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Accepted: 01/21/2025] [Indexed: 02/21/2025] Open
Abstract
Human leukocyte antigen (HLA) mismatching, particularly with HLA-DQ, significantly impacts the development of donor-specific antibodies (DSA) and transplant outcomes. HLA-DQ antibodies are highly immunogenic and detrimental, necessitating advanced high-resolution HLA typing to improve mismatch assessment and clinical risk evaluation. Traditional serological or low-resolution typing often misclassifies mismatches, leading to inaccuracies in assessing immunogenicity and predicting outcomes. Emerging molecular mismatch algorithms refine immunogenicity assessments by analyzing amino acid differences and structural interactions. These tools show promise for personalizing transplant protocols but have limitations, such as variability in predicting individual patient outcomes. Immunogenicity of mismatches also depends on evolutionary divergence and specific amino acid differences, with studies revealing that certain evolutionary lineages and polymorphisms influence T-cell alloreactivity and DSA development. Complexities in HLA-DQ protein expression, including combinatorial diversity of heterodimers and inter-isotypic heterodimers, further complicate risk evaluation. Expression levels, influenced by tissue specificity and inflammatory stimuli, and alternative splicing of HLA-DQ transcripts add additional layers of variability. Future clinical applications, enabled by high-resolution HLA typing, may include refined graft selection, improved DSA monitoring, and individualized therapy. However, understanding the precise mechanisms of HLA-DQ immunogenicity remains a priority for advancing transplantation science and enhancing patient outcomes.
Collapse
Affiliation(s)
- Rajdeep Das
- University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, United States
| | | |
Collapse
|
|
4
|
Kabátek J, Blanchard R. Birth Order and Family Size of UK Biobank Subjects Identified as Asexual, Bisexual, Heterosexual, or Homosexual According to Self-Reported Sexual Histories. ARCHIVES OF SEXUAL BEHAVIOR 2025; 54:35-50. [PMID: 39354277 PMCID: PMC11782301 DOI: 10.1007/s10508-024-03004-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 09/02/2024] [Accepted: 09/03/2024] [Indexed: 10/04/2024]
Abstract
This study used a recently developed statistical technique to investigate the relations between various elements of a subject's family background and the odds of that subject reporting a sexual history indicative of a minority sexual orientation. The subjects were 78,983 men and 92,150 women who completed relevant questionnaire items in the UK Biobank, a large-scale biomedical database of volunteers aged 40-69 years. The men were divided into three sexual minority groups-homosexual, bisexual, and asexual-and a comparison group of heterosexual men. The same was done for the women. The analytic procedure consisted of logistic regressions specifically designed to disentangle the effects of birth order and family size. The results showed that older brothers increased the odds of homosexuality in both men and women, and that older sisters increased the odds in men. In contrast, neither older brothers or older sisters affected the odds of bisexuality or asexuality in men or in women. These results suggest that birth order effects may be specific to homosexuality and not common to all minority orientations. The only family size finding was the negative association between family size and the odds of asexuality in both men and women. The outcomes of this study indicate that the maternal immune hypothesis, which was advanced to explain the relation between older brothers and homosexuality in later-born males, might have to be abandoned or else expanded to explain the findings concerning females. A few such modifications are considered.
Collapse
Affiliation(s)
- Jan Kabátek
- Melbourne Institute of Applied Economic and Social Research, The University of Melbourne, 111 Barry St., Carlton, Melbourne, VIC, 3053, Australia.
- ARC Centre of Excellence for Children and Families Over the Life Course, Brisbane, Australia.
- Institute of Labor Economics, Bonn, Germany.
- CentER, Tilburg University, Tilburg, The Netherlands.
| | - Ray Blanchard
- Department of Psychiatry, The University of Toronto, Toronto, ON, Canada
| |
Collapse
|
|
5
|
Pei Y, Li H, Huang C, Qin Y, Sun X. Associations between end stage renal disease and HLA polymorphisms in the Guangxi Zhuang population. Sci Rep 2024; 14:21765. [PMID: 39294236 PMCID: PMC11410959 DOI: 10.1038/s41598-024-72688-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Accepted: 09/10/2024] [Indexed: 09/20/2024] Open
Abstract
To investigate the genetic relationship between end stage renal disease (ESRD) and human leukocyte antigen (HLA) alleles in the Guangxi Zhuang population. We performed polymerase chain reaction reversed sequence-specific oligonucleotide (PCR-rSSO) in 325 patients with ESRD and genotyped the HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 loci. The direct counting method was used to determine the frequencies of HLA alleles, and Arlequin software (version 3.5.2.2) was used for haplotypic frequency analyses to compare the included ESRD patients with 350 healthy donors from the Guangxi Zhuang population. In our study, 120 HLA alleles, 284 HLA-A-B-DRB1 haplotypes, and 332 HLA-A-C-B-DRB1-DQB1 haplotypes were detected. We found that only A*11:01-B*15:02-DRB1*12:02 had a positive association with ESRD (P = 0.001, Pc = 0.020, OR = 3.106, 95% CI = 1.497-6.446) after Bonferroni correction; thus, individuals with this haplotype may be susceptible to ESRD. A*11:01-B*15:02-DRB1*12:02 is a potentially valuable haplotype for evaluating the risk of ESRD in the Guangxi Zhuang population.
Collapse
Affiliation(s)
- Yongfeng Pei
- School of Basic Medicine, Guangxi Medical University, Nanning, China
- Institute of Transplantation Medicine, The Second Affiliated Hospital of Guangxi Medical University. Guangxi Clinical Research Center for Organ Transplantation. Guangxi Key Laboratory of Organ Donation and Transplantation, Nanning, China
| | - Haibin Li
- Institute of Transplantation Medicine, The Second Affiliated Hospital of Guangxi Medical University. Guangxi Clinical Research Center for Organ Transplantation. Guangxi Key Laboratory of Organ Donation and Transplantation, Nanning, China
| | - Chengxin Huang
- Institute of Transplantation Medicine, The Second Affiliated Hospital of Guangxi Medical University. Guangxi Clinical Research Center for Organ Transplantation. Guangxi Key Laboratory of Organ Donation and Transplantation, Nanning, China
| | - Yinhong Qin
- Institute of Transplantation Medicine, The Second Affiliated Hospital of Guangxi Medical University. Guangxi Clinical Research Center for Organ Transplantation. Guangxi Key Laboratory of Organ Donation and Transplantation, Nanning, China
| | - Xuyong Sun
- Institute of Transplantation Medicine, The Second Affiliated Hospital of Guangxi Medical University. Guangxi Clinical Research Center for Organ Transplantation. Guangxi Key Laboratory of Organ Donation and Transplantation, Nanning, China.
| |
Collapse
|
|
6
|
Vagiotas L, Lioulios G, Panteli M, Ouranos K, Xochelli A, Kasimatis E, Nikolaidou V, Samali M, Daoudaki M, Katsanos G, Antoniadis N, Tsoulfas G, Stangou M, Fylaktou A. Kidney Transplantation and Cellular Immunity Dynamics: Immune Cell Alterations and Association with Clinical and Laboratory Parameters. J Clin Med 2024; 13:5093. [PMID: 39274306 PMCID: PMC11396483 DOI: 10.3390/jcm13175093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 08/23/2024] [Accepted: 08/25/2024] [Indexed: 09/16/2024] Open
Abstract
Background/Objectives: The purpose of this study was to evaluate numerical changes in immune cells after successful kidney transplantation and associate their recovery with clinical and laboratory factors. Methods: In 112 kidney transplant recipients, we performed flow cytometry to evaluate counts of CD4+, CD8+, and regulatory T cells (Tregs), as well as natural killer (NK) cells, before kidney transplantation (T0) and three (T3), six (T6), and twelve (T12) months later. The results were associated with the recipient's age, cold ischemia time (CIT), the type of donor, dialysis method and vintage, and graft function in one year. Results: Total and CD8+ T cell counts increased gradually one year post transplantation in comparison with pre-transplantation levels, whereas the number of CD4+ T cells and Tregs increased, and the number of NK cells decreased in the first three months and remained stable thereafter. The recipient's age was negatively correlated with total, CD4+, and Treg counts at T12, whereas CIT affected only total and CD4+ T cell count. Moreover, recipients receiving kidneys from living donors presented better recovery of all T cell subsets at T12 in comparison with recipients receiving kidneys from cadaveric donors. Patients on peritoneal dialysis had increased numbers of total and CD8+ T cells, as well as NK cells. Finally, estimated glomerular filtration rate was positively correlated with Treg level and potentially CD4+ T cells one-year post transplantation. Conclusions: Successful kidney transplantation results in the recovery of most T cell subsets. Lower recipient age and better graft function contribute to increased T cell counts, whereas donor type and dialysis modality are the most important modifiable factors for optimal immune recovery.
Collapse
Affiliation(s)
- Lampros Vagiotas
- Department of Transplant Surgery, General Hospital Hippokratio, 54642 Thessaloniki, Greece; (L.V.); (G.K.); (N.A.); (G.T.)
| | - Georgios Lioulios
- Department of Nephrology, 424 General Military Hospital of Thessaloniki, 56429 Thessaloníki, Greece
| | - Manolis Panteli
- 1st Department of Nephrology, General Hospital Hippokratio, 54642 Thessaloniki, Greece; (M.P.); (E.K.); (M.S.)
| | - Konstantinos Ouranos
- Department of Medicine, Houston Methodist Research Institute, Houston, TX 77030, USA;
| | - Aliki Xochelli
- National Peripheral Histocompatibility Center, Department of Immunology, General Hospital Hippokratio, 54642 Thessaloniki, Greece; (A.X.); (V.N.); (M.S.); (A.F.)
| | - Efstratios Kasimatis
- 1st Department of Nephrology, General Hospital Hippokratio, 54642 Thessaloniki, Greece; (M.P.); (E.K.); (M.S.)
| | - Vasiliki Nikolaidou
- National Peripheral Histocompatibility Center, Department of Immunology, General Hospital Hippokratio, 54642 Thessaloniki, Greece; (A.X.); (V.N.); (M.S.); (A.F.)
| | - Margarita Samali
- National Peripheral Histocompatibility Center, Department of Immunology, General Hospital Hippokratio, 54642 Thessaloniki, Greece; (A.X.); (V.N.); (M.S.); (A.F.)
| | - Maria Daoudaki
- School of Medicine, Aristotle University of Thessaloniki, 45636 Thessaloniki, Greece;
| | - Georgios Katsanos
- Department of Transplant Surgery, General Hospital Hippokratio, 54642 Thessaloniki, Greece; (L.V.); (G.K.); (N.A.); (G.T.)
| | - Nikolaos Antoniadis
- Department of Transplant Surgery, General Hospital Hippokratio, 54642 Thessaloniki, Greece; (L.V.); (G.K.); (N.A.); (G.T.)
| | - Georgios Tsoulfas
- Department of Transplant Surgery, General Hospital Hippokratio, 54642 Thessaloniki, Greece; (L.V.); (G.K.); (N.A.); (G.T.)
| | - Maria Stangou
- 1st Department of Nephrology, General Hospital Hippokratio, 54642 Thessaloniki, Greece; (M.P.); (E.K.); (M.S.)
- School of Medicine, Aristotle University of Thessaloniki, 45636 Thessaloniki, Greece;
| | - Asimina Fylaktou
- National Peripheral Histocompatibility Center, Department of Immunology, General Hospital Hippokratio, 54642 Thessaloniki, Greece; (A.X.); (V.N.); (M.S.); (A.F.)
| |
Collapse
|
|
7
|
Konno H, Miyamae J, Kataoka H, Akai M, Miida H, Tsuchiya Y. Dog leukocyte antigen genotyping across class I and class II genes in beagle dogs as laboratory animals. Immunogenetics 2024; 76:261-270. [PMID: 38922357 DOI: 10.1007/s00251-024-01344-w] [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: 03/06/2024] [Accepted: 06/19/2024] [Indexed: 06/27/2024]
Abstract
Dog leukocyte antigen (DLA) polymorphisms have been found to be associated with inter-individual variations in the risk, susceptibility, and severity of immune-related phenomena. While DLA class II genes have been extensively studied, less research has been performed on the polymorphisms of DLA class I genes, especially in beagle dogs commonly used as laboratory animals for safety evaluations in drug development. We genotyped four DLA class I genes and four DLA class II genes by locus-specific Sanger sequencing using 93 laboratory beagle dogs derived from two different strains: TOYO and Marshall. The results showed that, for DLA class I genes, 11, 4, 1, and 2 alleles, including a novel allele, were detected in DLA-88, DLA-12/88L, DLA-64, and DLA-79, while, for DLA class II genes, 1, 10, 6, and 7 alleles were detected in DLA-DRA, DLA-DRB1, DLA-DQA1, and DLA-DQB1, respectively. It was estimated that there were 14 DLA haplotypes, six of which had a frequency of ≥ 5%. Furthermore, when comparing the DLA diversity between TOYO and Marshall strains, the most common alleles and haplotypes differed between them. This is the first study to genotype all DLA loci and determine DLA haplotypes including all DLA class I and class II genes in dogs. Integrating information on the DLA diversity of laboratory beagle dogs should reinforce their benefit as an animal model for understanding various diseases associated with a specific DLA type.
Collapse
Affiliation(s)
- Hiroya Konno
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo, 134-8630, Japan.
| | - Jiro Miyamae
- Faculty of Veterinary Medicine, Okayama University of Science, 1-3 Ikoino-oka, Imabari, Japan
| | - Hiroko Kataoka
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo, 134-8630, Japan
| | - Makoto Akai
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo, 134-8630, Japan
| | - Hiroaki Miida
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo, 134-8630, Japan
| | - Yoshimi Tsuchiya
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo, 134-8630, Japan
| |
Collapse
|
|
8
|
Krishnan N, Briggs D. Imlifidase: Is it the Magic Wand in Renal Transplantation? Indian J Nephrol 2024; 34:291-296. [PMID: 39156835 PMCID: PMC11326793 DOI: 10.25259/ijn_325_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 09/15/2023] [Indexed: 08/20/2024] Open
Abstract
Potential kidney transplant patients with HLA-specific antibodies have reduced access to transplantation. Their harmful effects are mediated by the Fc portion of IgG, including activation of the complement system and Fc receptor-initiated cytotoxic processes by circulating leucocytes. Avoiding antibody incompatibility is the conventional approach, but for some patients this can mean extended waiting times, or even no chance of a transplant if there are no alternative, compatible donors. For these cases, pretransplant antibody removal may provide access to transplantation. Plasmapheresis is currently used to achieve this, with acceptable outcome results, but the process can take days to reduce the antibody levels to a safe level, so has limited use for deceased donors. There is now an alternative, in the form of an IgG-digesting enzyme, Imlifidase, which can be administered for in vivo IgG inactivation. Imlifidase cleaves human IgG, separating the antigen-binding part, F(ab')2 from Fc. Typically, within six hours of dosing, most, if not all, of the circulating IgG has been inactivated, allowing safe transplantation from a previously incompatible donor. For deceased donor transplantation, where minimizing cold ischaemia is critical, this six-hour delay before implantation should be manageable, with the compatibility testing processes adjusted to accommodate the treatment. This agent has been used successfully in phase 2 clinical trials, with good short to medium term outcomes. While a donation rate that matches demand may be one essential answer to providing universal access to kidney transplantation, this is currently unrealistic. IgG inactivation, using Imlifidase, is, however, a realistic and proven alternative.
Collapse
Affiliation(s)
- Nithya Krishnan
- Department of Renal and Transplant Medicine, Institute of Cardiometabolic Medicine, University of Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom
- Institute of Community and Health Care, Coventry University, Coventry, United Kingdom
| | - David Briggs
- Histocompatibility and Immunogenetics Lab, NHS Blood and Transplant, Birmingham, United Kingdom
- Institute of Immunology and Immunotherapy, University of Birmingham, Coventry, United Kingdom
| |
Collapse
|
|
9
|
Hakeem AR, Asthana S, Johnson R, Brown C, Ahmad N. Impact of Asian and Black Donor and Recipient Ethnicity on the Outcomes After Deceased Donor Kidney Transplantation in the United Kingdom. Transpl Int 2024; 37:12605. [PMID: 38711816 PMCID: PMC11070942 DOI: 10.3389/ti.2024.12605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Accepted: 04/09/2024] [Indexed: 05/08/2024]
Abstract
Patients of Asian and black ethnicity face disadvantage on the renal transplant waiting list in the UK, because of lack of human leucocyte antigen and blood group matched donors from an overwhelmingly white deceased donor pool. This study evaluates outcomes of renal allografts from Asian and black donors. The UK Transplant Registry was analysed for adult deceased donor kidney only transplants performed between 2001 and 2015. Asian and black ethnicity patients constituted 12.4% and 6.7% of all deceased donor recipients but only 1.6% and 1.2% of all deceased donors, respectively. Unadjusted survival analysis demonstrated significantly inferior long-term allograft outcomes associated with Asian and black donors, compared to white donors. On Cox-regression analysis, Asian donor and black recipient ethnicities were associated with poorer outcomes than white counterparts, and on ethnicity matching, compared with the white donor-white recipient baseline group and adjusting for other donor and recipient factors, 5-year graft outcomes were significantly poorer for black donor-black recipient, Asian donor-white recipient, and white donor-black recipient combinations in decreasing order of worse unadjusted 5-year graft survival. Increased deceased donation among ethnic minorities could benefit the recipient pool by increasing available organs. However, it may require a refined approach to enhance outcomes.
Collapse
Affiliation(s)
- Abdul Rahman Hakeem
- Division of Surgery, Department of Transplantation, St. James’s University Hospital, Leeds, United Kingdom
| | - Sonal Asthana
- Division of Surgery, Department of Transplantation, St. James’s University Hospital, Leeds, United Kingdom
| | - Rachel Johnson
- National Health Service Blood and Transplant (NHSBT), Bristol, United Kingdom
| | - Chloe Brown
- National Health Service Blood and Transplant (NHSBT), Bristol, United Kingdom
| | - Niaz Ahmad
- King Faisal Specialist Hospital and Research Centre, Jeddah, Saudi Arabia
| |
Collapse
|
|
10
|
Pasilan RMF, Villanueva ART. Presumed Monozygotic Twin Kidney Transplantation with a Thin Basement Membrane Nephropathy Donor: A Case Report. ACTA MEDICA PHILIPPINA 2024; 58:68-73. [PMID: 39005620 PMCID: PMC11239991 DOI: 10.47895/amp.vi0.7099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 07/16/2024]
Abstract
Identical or Monozygotic twin kidney transplant usually possess an excellent immunological match and provide the opportunity to minimize or even avoid immunosuppression toxicity. However, there are concerns regarding disease recurrence among end stage kidney disease (ESKD) patients with an unknown etiology. Together with the risk of inherent, familial disease affecting donors and recipients alike, more invasive tests such as a pretransplant biopsy are being considered to ascertain renal prognosis. A 30-year-old female, known case of CKD Stage 5D from an unknown etiology, with secondary hyperparathyroidism and heart failure, presented at our OPD for kidney transplantation. Her donor is her identical twin who is asymptomatic and denies comorbidities. The recipient discloses a previous history of blood transfusion. Immunological workup revealed the following: matched blood type, zero HLA mismatch, negative T-cell tissue crossmatch but with a positive Class I HLA antigen screen. Antibody specificity revealed the presence of donor specific antibodies (DSA). After workup completion, the patient underwent a right kidney transplant with a preimplantation wedge biopsy on the donor kidney. Immediate graft function was noted post operatively. The wedge biopsy revealed a thinned glomerular basement membrane, consistent with Thin Basement Membrane Nephropathy (TBMN). The patient was started on immunosuppression and prophylaxis during the duration of the post operative period without any complications. Five months post-transplant, both the recipient and donor maintain an adequate renal function without any signs of allograft rejection. In this case report, we have demonstrated that TBMN may serve as a viable donor for a presumed monozygous twin kidney transplantation. When a live donor with TBMN is being considered, a thorough work-up and identification of high-risk features are essential to exclude other progressive renal diseases during the pretransplant evaluation.
Collapse
Affiliation(s)
- Renz Michael F Pasilan
- Division of Nephrology, Department of Medicine, Philippine General Hospital, University of the Philippines Manila
| | - Anthony Russell T Villanueva
- Division of Nephrology, Department of Medicine, Philippine General Hospital, University of the Philippines Manila
| |
Collapse
|
|
11
|
Baudouin R, Von Tokarski F, Rigal T, Crambert A, Hertig A, Hans S. Immunosuppressive protocols after laryngeal transplantation: a systematic review. Acta Otolaryngol 2024; 144:243-249. [PMID: 38662869 DOI: 10.1080/00016489.2024.2339341] [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: 03/13/2024] [Accepted: 03/28/2024] [Indexed: 06/20/2024]
Abstract
BACKGROUNDS Larynx transplantation has been successfully performed four times, in 1998, 2010, 2015 and 2023 remained the ultimate goal of voice, feeding and breathing rehabilitation. OBJECTIVE Immunosuppressive protocols used during the previous successful larynx allotransplantation are detailed. MATERIAL AND METHODS A systematic review of the literature on PUBMED/Medline, Cochrane and Embase was conducted. Articles relating to actual human larynx transplantations were included. RESULTS Bibliography search gathered N = 10 publications related to the performance and follow-up of human laryngeal transplantations. N = 8 publications were included corresponding to N = 3 actual human larynx transplantations performed in 1998 and 2010 in the USA and in 2015 in Poland. Immunosuppression protocols, induction and maintenance strategies, rejection monitoring and history of all the three previous laryngeal grafts were detailed. CONCLUSIONS Beyond the surgical prowess, larynx transplantation is feasible and associated with a reasonably successful outcome when compared to other solid organ transplants. Immunosuppressive regimen protocols and technologies for the monitoring of the organ viability have evolved. SIGNIFICANCE The reevaluation of this surgical option serves as the reminder of the critical necessity to implement a meticulous immunosuppression protocol when transplanting this inherently immunogenic composite organ, the larynx.
Collapse
Affiliation(s)
- Robin Baudouin
- Department of Otolaryngology‑Head & Neck Surgery, Foch Hospital, School of Medicine, UFR Simone Veil, Université Versailles Saint-Quentin-en-Yvelines (Université Paris Saclay), Montigny‑le‑Bretonneux, France
| | - Florent Von Tokarski
- Department of Nephrology, Foch Hospital, School of Medicine, UFR Simone Veil, Université Versailles Saint-Quentin-en-Yvelines (Université Paris Saclay), Montigny‑le‑Bretonneux, France
| | - Tiffany Rigal
- Department of Otolaryngology‑Head & Neck Surgery, Foch Hospital, School of Medicine, UFR Simone Veil, Université Versailles Saint-Quentin-en-Yvelines (Université Paris Saclay), Montigny‑le‑Bretonneux, France
| | - Anna Crambert
- Department of ENT Head and Neck Surgery, Percy Military Training Hospital, Clamart, France
| | - Alexandre Hertig
- Department of Nephrology, Foch Hospital, School of Medicine, UFR Simone Veil, Université Versailles Saint-Quentin-en-Yvelines (Université Paris Saclay), Montigny‑le‑Bretonneux, France
| | - Stéphane Hans
- Department of Otolaryngology‑Head & Neck Surgery, Foch Hospital, School of Medicine, UFR Simone Veil, Université Versailles Saint-Quentin-en-Yvelines (Université Paris Saclay), Montigny‑le‑Bretonneux, France
- Phonetics and Phonology Laboratory (UMR 7018 CNRS, Université Sorbonne Nouvelle/Paris 3), Paris, France
| |
Collapse
|
|
12
|
Kavuzlu M, Zengel B, Baştürk B. HLA-B*51 Frequency in Transplant Patients and Donors. EXP CLIN TRANSPLANT 2024; 22:265-269. [PMID: 38385410 DOI: 10.6002/ect.mesot2023.p76] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/23/2024]
Abstract
OBJECTIVES HLA molecules play a crucial role in transplantation. The best treatment modality in patients with end-stage renal disease is renal transplant. HLA mismatches between patients and donors can prolong time for renal transplant therapy, reduce graft survival, and increase mortality. HLA region is the most polymorphic genetic region and is essential for antigen presentation. The main target of the recipient's immune system is HLA molecules on the surface of donor cells. HLA-B*51 is associated with Behcet disease, a rare multisystemic disease characterized by autoimmunity and inflammatory processes. In transplant recipients, inflammation and vasculitis are immunologic mechanisms that are responsible for damage of graft tissue. In this retrospective study, we aimed to investigate the frequency of HLA-B*51 in patients diagnosed with end-stage renal disease and in controls and to investigate correlations with rejection episodes. MATERIALS AND METHODS Patients who applied to Baskent University Adana Dr. Turgut Noyan Research and Medical Center (between 2010 and 2022) with end-stage renal disease (n = 1732) and a control group (n = 5277) received HLA typing for class I (HLA-A, HLA-B). Sequence-specific primers or sequencespecific oligonucleotides were used. Among patients diagnosed with end-stage renal disease, 321 had kidney transplant. RESULTS Frequency of HLA-B*51 was 25.92% in patients and 25.22% in controls. No significant differences were found between patients and controls in the frequency of HLA-B*51. Among kidney transplant recipients with HLA-B*51 (n = 72), 38.89% had rejection episodes and 61.11% had no rejection. No significant association was found between HLA-B*51 allele positivity and rejection. CONCLUSIONS No significant relationship was shown between patients diagnosed with end-stage renal disease and HLA-B*51 positivity. Previous studies support frequency of the HLA-B*51 allele in the control group. Although Behçet disease is known to cause renal vasculitis, HLA-B*51 positivity alone was not associated with vasculitis or inflammation.
Collapse
Affiliation(s)
- Miray Kavuzlu
- From the Transplantation Immunology-Tissue Typing Laboratory, Adana Research and Medical Center, Baskent University, Adana, Turkey; and the Department of Medical Biology, Baskent University, Ankara, Turkey
| | | | | |
Collapse
|
|
13
|
Tiwari A, Mukherjee S. Role of Complement-dependent Cytotoxicity Crossmatch and HLA Typing in Solid Organ Transplant. Rev Recent Clin Trials 2024; 19:34-52. [PMID: 38155466 DOI: 10.2174/0115748871266738231218145616] [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: 07/05/2023] [Revised: 11/10/2023] [Accepted: 11/10/2023] [Indexed: 12/30/2023]
Abstract
BACKGROUND Solid organ transplantation is a life-saving medical operation that has progressed greatly because of developments in diagnostic tools and histocompatibility tests. Crossmatching for complement-dependent cytotoxicity (CDC) and human leukocyte antigen (HLA) typing are two important methods for checking graft compatibility and reducing the risk of graft rejection. HLA typing and CDC crossmatching are critical in kidney, heart, lung, liver, pancreas, intestine, and multi-organ transplantation. METHODS A systematic literature search was conducted on the internet, using PubMed, Scopus, and Google Scholar databases, to identify peer-reviewed publications about solid organ transplants, HLA typing, and CDC crossmatching. CONCLUSION Recent advances in HLA typing have allowed for high-resolution evaluation, epitope matching, and personalized therapy methods. Genomic profiling, next-generation sequencing, and artificial intelligence have improved HLA typing precision, resulting in better patient outcomes. Artificial intelligence (AI) driven virtual crossmatching and predictive algorithms have eliminated the requirement for physical crossmatching in the context of CDC crossmatching, boosting organ allocation and transplant efficiency. This review elaborates on the importance of HLA typing and CDC crossmatching in solid organ transplantation.
Collapse
Affiliation(s)
- Arpit Tiwari
- Amity Institute of Biotechnology, Amity University Uttar Pradesh Lucknow Campus, Lucknow, Uttar Pradesh, India
| | - Sayali Mukherjee
- Amity Institute of Biotechnology, Amity University Uttar Pradesh Lucknow Campus, Lucknow, Uttar Pradesh, India
| |
Collapse
|
|
14
|
Karpov DS, Sosnovtseva AO, Pylina SV, Bastrich AN, Petrova DA, Kovalev MA, Shuvalova AI, Eremkina AK, Mokrysheva NG. Challenges of CRISPR/Cas-Based Cell Therapy for Type 1 Diabetes: How Not to Engineer a "Trojan Horse". Int J Mol Sci 2023; 24:17320. [PMID: 38139149 PMCID: PMC10743607 DOI: 10.3390/ijms242417320] [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: 11/03/2023] [Revised: 12/04/2023] [Accepted: 12/07/2023] [Indexed: 12/24/2023] Open
Abstract
Type 1 diabetes mellitus (T1D) is an autoimmune disease caused by the destruction of insulin-producing β-cells in the pancreas by cytotoxic T-cells. To date, there are no drugs that can prevent the development of T1D. Insulin replacement therapy is the standard care for patients with T1D. This treatment is life-saving, but is expensive, can lead to acute and long-term complications, and results in reduced overall life expectancy. This has stimulated the research and development of alternative treatments for T1D. In this review, we consider potential therapies for T1D using cellular regenerative medicine approaches with a focus on CRISPR/Cas-engineered cellular products. However, CRISPR/Cas as a genome editing tool has several drawbacks that should be considered for safe and efficient cell engineering. In addition, cellular engineering approaches themselves pose a hidden threat. The purpose of this review is to critically discuss novel strategies for the treatment of T1D using genome editing technology. A well-designed approach to β-cell derivation using CRISPR/Cas-based genome editing technology will significantly reduce the risk of incorrectly engineered cell products that could behave as a "Trojan horse".
Collapse
Affiliation(s)
- Dmitry S. Karpov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (D.S.K.); (A.O.S.); (M.A.K.); (A.I.S.)
| | - Anastasiia O. Sosnovtseva
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (D.S.K.); (A.O.S.); (M.A.K.); (A.I.S.)
| | - Svetlana V. Pylina
- Endocrinology Research Centre, 115478 Moscow, Russia; (S.V.P.); (A.N.B.); (D.A.P.); (A.K.E.)
| | - Asya N. Bastrich
- Endocrinology Research Centre, 115478 Moscow, Russia; (S.V.P.); (A.N.B.); (D.A.P.); (A.K.E.)
| | - Darya A. Petrova
- Endocrinology Research Centre, 115478 Moscow, Russia; (S.V.P.); (A.N.B.); (D.A.P.); (A.K.E.)
| | - Maxim A. Kovalev
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (D.S.K.); (A.O.S.); (M.A.K.); (A.I.S.)
| | - Anastasija I. Shuvalova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (D.S.K.); (A.O.S.); (M.A.K.); (A.I.S.)
| | - Anna K. Eremkina
- Endocrinology Research Centre, 115478 Moscow, Russia; (S.V.P.); (A.N.B.); (D.A.P.); (A.K.E.)
| | - Natalia G. Mokrysheva
- Endocrinology Research Centre, 115478 Moscow, Russia; (S.V.P.); (A.N.B.); (D.A.P.); (A.K.E.)
| |
Collapse
|
|
15
|
Thakur S, Dandar R, Restaino IG, Cheung AY. Refractory Keratolimbal Allograft Rejection in Autoimmune Polyglandular Syndrome-Associated Keratopathy Treated With Intravenous Immunoglobulin. Cornea 2023; 42:747-750. [PMID: 36728304 DOI: 10.1097/ico.0000000000003229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Accepted: 11/25/2022] [Indexed: 02/03/2023]
Abstract
PURPOSE The aim of this study was to describe the use of intravenous immunoglobulin (IVIG) in the management of a 20-year-old woman with autoimmune polyglandular syndrome-associated keratopathy who developed acute transplant rejection after keratolimbal allograft (KLAL) surgery. CASE Nine weeks after KLAL surgery, a 20-year-old woman with autoimmune polyglandular syndrome-related limbal stem cell deficiency presented with graft injection, hemorrhage, and an epithelial rejection line. This was concerning for acute rejection in the setting of triple-agent systemic immunosuppression (albeit nonadherence at times). There was initial reversal of the rejection process with a sub-Tenon's injection of triamcinolone, frequent topical corticosteroids, increase in oral prednisone, and optimization of systemic immunosuppression medications; however, recurrence of the epithelial rejection line and symptoms were noted whenever the prednisone dose was tapered. This was accompanied by ocular surface decompensation (late staining, neovascularization, and persistent epithelial defects). She was found to have weakly positive HLA Class 1 antibodies. The patient was treated with a pulsed corticosteroid infusion and 2 monthly IVIG infusions. This led to resolution of the acute rejection. However, there was a subsequent rejection episode 4 months later after tapering the prednisone. Monthly IVIG for 6 more months led to final resolution with successful prednisone tapering and no further rejection. CONCLUSIONS Treatment with prolonged IVIG showed better improvement in a case of acute rejection refractory to traditional treatments, especially in the setting of HLA antibodies. The case demonstrates that close follow-up with a corneal specialist and collaboration with a transplant specialist is important to monitor for postoperative KLAL rejection.
Collapse
Affiliation(s)
- Shambhawi Thakur
- Department of Ophthalmology, Eastern Virginia Medical School, Norfolk, VA
| | - Rachel Dandar
- Department of Ophthalmology, Eastern Virginia Medical School, Norfolk, VA
| | - Irene G Restaino
- Department of Pediatrics (Nephrology), Children's Hospital of The King's Daughters, Norfolk, VA; and
| | - Albert Y Cheung
- Department of Ophthalmology, Eastern Virginia Medical School, Norfolk, VA
- Department of Ophthalmology, Eastern Virginia Medical School, Virginia Eye Consultants/CVP Physicians, Norfolk, VA
| |
Collapse
|
|
16
|
Elalouf A. Infections after organ transplantation and immune response. Transpl Immunol 2023; 77:101798. [PMID: 36731780 DOI: 10.1016/j.trim.2023.101798] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 01/08/2023] [Accepted: 01/26/2023] [Indexed: 01/31/2023]
Abstract
Organ transplantation has provided another chance of survival for end-stage organ failure patients. Yet, transplant rejection is still a main challenging factor. Immunosuppressive drugs have been used to avoid rejection and suppress the immune response against allografts. Thus, immunosuppressants increase the risk of infection in immunocompromised organ transplant recipients. The infection risk reflects the relationship between the nature and severity of immunosuppression and infectious diseases. Furthermore, immunosuppressants show an immunological impact on the genetics of innate and adaptive immune responses. This effect usually reactivates the post-transplant infection in the donor and recipient tissues since T-cell activation has a substantial role in allograft rejection. Meanwhile, different infections have been found to activate the T-cells into CD4+ helper T-cell subset and CD8+ cytotoxic T-lymphocyte that affect the infection and the allograft. Therefore, the best management and preventive strategies of immunosuppression, antimicrobial prophylaxis, and intensive medical care are required for successful organ transplantation. This review addresses the activation of immune responses against different infections in immunocompromised individuals after organ transplantation.
Collapse
Affiliation(s)
- Amir Elalouf
- Bar-Ilan University, Department of Management, Ramat Gan 5290002, Israel.
| |
Collapse
|
|
17
|
Guo Y, Zheng B, Tian P, Zheng J, Li Y, Ding X, Xue W, Ding C. HLA class II antibody activation of endothelial cells induces M2 macrophage differentiation in peripheral blood. Clin Exp Nephrol 2023; 27:309-320. [PMID: 36611129 DOI: 10.1007/s10157-022-02307-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 11/30/2022] [Indexed: 01/09/2023]
Abstract
BACKGROUND Donor-specific human leukocyte antigen (HLA) class II antibodies (HLA-II Abs) combined with allogeneic endothelial cells (ECs) mediate high-risk rejection in kidney transplant patients. Macrophage accumulation is a significant histological feature of antibody-mediated rejection (AMR) in kidney transplant patients. Here, we further investigated the effect of HLA-II Abs on macrophage phenotypes to provide theoretical basis for clinical treatment of AMR. METHODS We prepared an experimental model containing HLA-II Ab-stimulated microvascular ECs and peripheral blood mononuclear cells (PBMCs) co-culture and explored the potential relationship of HLA-II Ab, ECs activation, and macrophage differentiation. Immune phenotype of macrophage subsets was analyzed and quantified by flow cytometry. HLA-II Ab activation of ECs induces M2 macrophage differentiation signal pathways which were investigated by qPCR and western blotting. RESULTS The stimulation of ECs by F(ab')2 fragment of HLA-II Abs led to phosphorylation of PI3K, Akt, and mTOR, which mediated IL-10, ICAM-1, VCAM-1 secretion. The enhanced ICAM-1 and IL-10 promoted the migration of PBMCs and their differentiation into CD68+ and CD163+ (M2-type) macrophages, respectively, but not CD86+ macrophages. CONCLUSION These findings revealed the PI3K/Akt/mTOR signal pathways activated by HLA-II Abs in ECs and the immune regulation ability of HLA-II Abs to induce PBMC differentiation.
Collapse
Affiliation(s)
- Yingcong Guo
- Department of Kidney Transplantation, Nephropathy Hospital, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 West Yanta Road, Xi'an, 710061, China
| | - Bingxuan Zheng
- Department of Kidney Transplantation, Nephropathy Hospital, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 West Yanta Road, Xi'an, 710061, China
| | - Puxun Tian
- Department of Kidney Transplantation, Nephropathy Hospital, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 West Yanta Road, Xi'an, 710061, China
- Institute of Organ Transplantation, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Jin Zheng
- Department of Kidney Transplantation, Nephropathy Hospital, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 West Yanta Road, Xi'an, 710061, China
- Institute of Organ Transplantation, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Yang Li
- Department of Kidney Transplantation, Nephropathy Hospital, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 West Yanta Road, Xi'an, 710061, China
- Institute of Organ Transplantation, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Xiaoming Ding
- Department of Kidney Transplantation, Nephropathy Hospital, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 West Yanta Road, Xi'an, 710061, China
- Institute of Organ Transplantation, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Wujun Xue
- Department of Kidney Transplantation, Nephropathy Hospital, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 West Yanta Road, Xi'an, 710061, China
- Institute of Organ Transplantation, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Chenguang Ding
- Department of Kidney Transplantation, Nephropathy Hospital, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 West Yanta Road, Xi'an, 710061, China.
- Institute of Organ Transplantation, Xi'an Jiaotong University, Xi'an, 710061, China.
| |
Collapse
|
|
18
|
Joshi I, Carney WP, Rock EP. Utility of monocyte HLA-DR and rationale for therapeutic GM-CSF in sepsis immunoparalysis. Front Immunol 2023; 14:1130214. [PMID: 36825018 PMCID: PMC9942705 DOI: 10.3389/fimmu.2023.1130214] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 01/16/2023] [Indexed: 02/09/2023] Open
Abstract
Sepsis, a heterogeneous clinical syndrome, features a systemic inflammatory response to tissue injury or infection, followed by a state of reduced immune responsiveness. Measurable alterations occur in both the innate and adaptive immune systems. Immunoparalysis, an immunosuppressed state, associates with worsened outcomes, including multiple organ dysfunction syndrome, secondary infections, and increased mortality. Multiple immune markers to identify sepsis immunoparalysis have been proposed, and some might offer clinical utility. Sepsis immunoparalysis is characterized by reduced lymphocyte numbers and downregulation of class II human leukocyte antigens (HLA) on innate immune monocytes. Class II HLA proteins present peptide antigens for recognition by and activation of antigen-specific T lymphocytes. One monocyte class II protein, mHLA-DR, can be measured by flow cytometry. Downregulated mHLA-DR indicates reduced monocyte responsiveness, as measured by ex-vivo cytokine production in response to endotoxin stimulation. Our literature survey reveals low mHLA-DR expression on peripheral blood monocytes correlates with increased risks for infection and death. For mHLA-DR, 15,000 antibodies/cell appears clinically acceptable as the lower limit of immunocompetence. Values less than 15,000 antibodies/cell are correlated with sepsis severity; and values at or less than 8000 antibodies/cell are identified as severe immunoparalysis. Several experimental immunotherapies have been evaluated for reversal of sepsis immunoparalysis. In particular, sargramostim, a recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF), has demonstrated clinical benefit by reducing hospitalization duration and lowering secondary infection risk. Lowered infection risk correlates with increased mHLA-DR expression on peripheral blood monocytes in these patients. Although mHLA-DR has shown promising utility for identifying sepsis immunoparalysis, absence of a standardized, analytically validated method has thus far prevented widespread adoption. A clinically useful approach for patient inclusion and identification of clinically correlated output parameters could address the persistent high unmet medical need for effective targeted therapies in sepsis.
Collapse
Affiliation(s)
- Ila Joshi
- Development and Regulatory Department, Partner Therapeutics, Inc., Lexington, MA, United States,*Correspondence: Ila Joshi,
| | - Walter P. Carney
- Walt Carney Biomarkers Consulting, LLC., North Andover, MA, United States
| | - Edwin P. Rock
- Development and Regulatory Department, Partner Therapeutics, Inc., Lexington, MA, United States
| |
Collapse
|
|
19
|
Kardol-Hoefnagel T, Michielsen LA, Ehlers AM, van Zuilen AD, Luijk B, Otten HG. Complement component C3 and C5b-9 deposition on hypoxia reperfused endothelial cells by non-HLA antibodies against RhoGDI2: A player involved in graft failure? HLA 2023; 101:103-114. [PMID: 36266772 PMCID: PMC10091817 DOI: 10.1111/tan.14858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 09/23/2022] [Accepted: 10/18/2022] [Indexed: 01/25/2023]
Abstract
Antibodies against Rho GDP-dissociation inhibitor 2 (RhoGDI2) are associated with inferior graft survival in transplant patients receiving a kidney from deceased donors. Although this suggests that these antibodies contribute to graft injury because of ischemia, it remains unknown whether they are also pathogenically involved in the process of graft loss. To study this, we firstly analyzed the IgG subclass profile of anti-RhoGDI2 antibodies in kidney transplant recipients, and whether antibody titers change over time or because of acute rejection. Next, we investigated the expression of RhoGDI2 on primary kidney and lung endothelial cells (ECs) upon hypoxia reperfusion. In addition, the complement-fixing properties of anti-RhoGDI2 antibodies were studied using imaging flow cytometry. Anti-RhoGDI2 antibodies in patients are mainly IgG1, and titers remained stable and seemed not be changed because of rejection. Antibodies against RhoGDI2, which surface expression seemed to increase upon hypoxia reperfusion, co-localized with C3 on ECs. Binding of human IgG1 monoclonal anti-RhoGDI2 antibodies as well as patient derived antibodies, resulted in complement activation, suggesting that these antibodies are complement fixing. This study suggested a potential pathogenic role of anti-RhoGDI2 antibodies in kidney graft loss. During ischemia reperfusion, the ability of these antibodies to fix complement could be one of the mechanisms resulting in tissue injury.
Collapse
Affiliation(s)
- Tineke Kardol-Hoefnagel
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Laura A Michielsen
- Department of Nephrology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Anna M Ehlers
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.,Department of Dermatology/Allergology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Arjan D van Zuilen
- Department of Nephrology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Bart Luijk
- Department of Respiratory Medicine, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Henny G Otten
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
| |
Collapse
|
|
20
|
Stored whole blood transfusion initiates serum amyloid A activation monitored by real-time dynamic imaging. BLOOD TRANSFUSION = TRASFUSIONE DEL SANGUE 2023; 21:62-73. [PMID: 35302477 PMCID: PMC9918385 DOI: 10.2450/2022.0259-21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 01/17/2022] [Indexed: 02/12/2023]
Abstract
BACKGROUND Transfusion of stored whole blood (SWB) to resuscitate severe traumatic haemorrhage patients in military operations and civilian emergency centres is being increasingly used in routine practice. It has been well established that transfusion of red blood cells (RBCs) after prolonged storage has harmful effects, mainly mediated by inflammation. Whether the side effects of inflammation are brought about by SWB transfusion remains unclear. MATERIALS AND METHODS A hepatocyte SAA (serum amyloid A) specific reporter mouse that facilitated non-invasive imaging of hepatocyte SAA expression was used to evaluate acute inflammation and acute-phase reaction after the transfusion of SWB or components separated from end-storage whole blood. The whole blood of C57BL/6 donor mouse was used to model an allogeneic transfusion to BALB/c recipient mouse. RESULTS End-storage whole blood (14 days of storage) transfusion induced the most significant SAA expression, while 10-day storage resulted in a much weaker signal compared to their fresh and 5-day storage counterparts. RBCs rather than white blood cells and plasma-containing platelets are thought to be responsible for the systemic inflammatory and SAA activation during end-storage whole blood transfusion. Circulatory and hepatic pro-inflammatory cytokines secreted by M1-polarised macrophage initiated the SAA expression in hepatocytes through nuclear transcription factor NF-κB. DISCUSSION Storage lesions will also occur during the storage of whole blood, which is related to the change in RBCs with prolonged storage. The side effect induced by systemic inflammation and acute-phase reaction should be considered before resuscitation with long-term storage whole blood transfusion.
Collapse
|
|
21
|
Bharadwaj P, Shrestha S, Pongracz T, Concetta C, Sharma S, Le Moine A, de Haan N, Murakami N, Riella LV, Holovska V, Wuhrer M, Marchant A, Ackerman ME. Afucosylation of HLA-specific IgG1 as a potential predictor of antibody pathogenicity in kidney transplantation. Cell Rep Med 2022; 3:100818. [PMID: 36384101 PMCID: PMC9729883 DOI: 10.1016/j.xcrm.2022.100818] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 08/23/2022] [Accepted: 10/17/2022] [Indexed: 11/17/2022]
Abstract
Antibody-mediated rejection (AMR) is the leading cause of graft failure. While donor-specific antibodies (DSAs) are associated with a higher risk of AMR, not all patients with DSAs develop rejection, suggesting that the characteristics of alloantibodies determining their pathogenicity remain undefined. Using human leukocyte antigen (HLA)-A2-specific antibodies as a model, we apply systems serology tools to investigate qualitative features of immunoglobulin G (IgG) alloantibodies including Fc-glycosylation patterns and FcγR-binding properties. Levels of afucosylated anti-A2 antibodies are elevated in seropositive patients, especially those with AMR, suggesting potential cytotoxicity via FcγRIII-mediated mechanisms. Afucosylation of both glycoengineered monoclonal and naturally glycovariant polyclonal serum IgG specific to HLA-A2 drives potentiated binding to, slower dissociation from, and enhanced signaling through FcγRIII, a receptor widely expressed on innate effector cells, and greater cytotoxicity against HLA-A2+ cells mediated by natural killer (NK) cells. Collectively, these results suggest that afucosylated DSA may be a biomarker of AMR and contribute to pathogenesis.
Collapse
Affiliation(s)
- Pranay Bharadwaj
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Dartmouth College, Hanover, NH 03755, USA
| | - Sweta Shrestha
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Dartmouth College, Hanover, NH 03755, USA
| | - Tamas Pongracz
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands
| | - Catalano Concetta
- Institute for Medical Immunology, Université Libre de Bruxelles, Charleroi, Belgium; Department of Nephrology, Dialysis and Renal Transplantation, Hôpital Erasme, Université libre de Bruxelles, Bruxelles, Belgium
| | - Shilpee Sharma
- Institute for Medical Immunology, Université Libre de Bruxelles, Charleroi, Belgium
| | - Alain Le Moine
- Department of Nephrology, Dialysis and Renal Transplantation, Hôpital Erasme, Université libre de Bruxelles, Bruxelles, Belgium
| | - Noortje de Haan
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands
| | - Naoka Murakami
- Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Leonardo V Riella
- Division of Nephrology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Vanda Holovska
- HLA Laboratory, Laboratoire Hospitalier Universitaire de Bruxelles (LHUB), Hôpital Erasme ULB, Brussels, Belgium
| | - Manfred Wuhrer
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands
| | - Arnaud Marchant
- Institute for Medical Immunology, Université Libre de Bruxelles, Charleroi, Belgium
| | - Margaret E Ackerman
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Dartmouth College, Hanover, NH 03755, USA; Thayer School of Engineering, Dartmouth College, Hanover, NH 03755, USA.
| |
Collapse
|
|
22
|
Muacevic A, Adler JR. Classic and Current Opinions in Human Organ and Tissue Transplantation. Cureus 2022; 14:e30982. [PMID: 36337306 PMCID: PMC9624478 DOI: 10.7759/cureus.30982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/01/2022] [Indexed: 11/30/2022] Open
Abstract
Graft tolerance is a pathophysiological condition heavily reliant on the dynamic interaction of the innate and adaptive immune systems. Genetic polymorphism determines immune responses to tissue/organ transplantation, and intricate humoral and cell-mediated mechanisms control these responses. In transplantation, the clinician's goal is to achieve a delicate equilibrium between the allogeneic immune response, undesired effects of the immunosuppressive drugs, and the existing morbidities that are potentially life-threatening. Transplant immunopathology involves sensitization, effector, and apoptosis phases which recruit and engages immunological cells like natural killer cells, lymphocytes, neutrophils, and monocytes. Similarly, these cells are involved in the transfer of normal or genetically engineered T cells. Advances in tissue transplantation would involve a profound knowledge of the molecular mechanisms that underpin the respective immunopathology involved and the design of precision medicines that are safe and effective.
Collapse
|
|
23
|
Vagiotas L, Stangou M, Kasimatis E, Xochelli A, Myserlis G, Lioulios G, Nikolaidou V, Panteli M, Ouranos K, Antoniadis N, Maria D, Papagianni A, Tsoulfas G, Fylaktou A. Effect of panel reactive antibodies on T cell immunity reinstatement following renal transplantation. World J Transplant 2022; 12:313-324. [PMID: 36313234 PMCID: PMC9614585 DOI: 10.5500/wjt.v12.i10.313] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 08/05/2022] [Accepted: 09/09/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Chronic kidney disease is associated with immunological disorders, presented as phenotypic alterations of T lymphocytes. These changes are expected to be restored after a successful renal transplantation; however, additional parameters may contribute to this process. AIM To evaluate the impact of positive panel reactive antibodies (PRAs) on the restoration of T cell phenotype, after renal transplantation. METHODS CD4CD28null, CD8CD28null, natural killer cells (NKs), and regulatory T cells (Tregs) were estimated by flow cytometry at T0, T3, and T6 which were the time of transplantation, and 3- and 6-mo follow-up, respectively. Changes were esti mated regarding the presence or absence of PRAs. RESULTS Patients were classified in two groups: PRA(-) (n = 43) and PRA(+) (n = 28) groups. Lymphocyte and their subtypes were similar between the two groups at T0, whereas their percentage was increased at T3 in PRA(-) compared to PRA(+) [23 (10.9-47.9) vs 16.4 (7.5-36.8 μ/L, respectively; P = 0.03]. Lymphocyte changes in PRA(-) patients included a significant increase in CD4 cells (P < 0.0001), CD8 cells (P < 0.0001), and Tregs (P < 0.0001), and a reduction of NKs (P < 0.0001). PRA(+) patients showed an increase in CD4 (P = 0.008) and CD8 (P = 0.0001), and a reduction in NKs (P = 0.07). CD4CD28null and CD8CD28null cells, although initially reduced in both groups, were stabilized thereafter. CONCLUSION Our study described important differences in the immune response between PRA(+) and PRA(-) patients with changes in lymphocytes and lymphocyte subpopulations. PRA(+) patients seemed to have a worse immune profile after 6 mo follow-up, regardless of renal function.
Collapse
Affiliation(s)
- Lampros Vagiotas
- Department of Transplant Surgery, School of Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Maria Stangou
- Department of Nephrology, School of Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Efstratios Kasimatis
- Department of Nephrology, School of Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Aliki Xochelli
- Department of Immunology, National Peripheral Histocompatibility Center, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Grigorios Myserlis
- Department of Transplant Surgery, School of Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Georgios Lioulios
- Department of Nephrology, School of Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Vasiliki Nikolaidou
- Department of Immunology, National Peripheral Histocompatibility Center, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Manolis Panteli
- Department of Nephrology, School of Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Konstantinos Ouranos
- Department of Nephrology, School of Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Nikolaos Antoniadis
- Department of Transplant Surgery, School of Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Daoudaki Maria
- Medical School Aristotle University of Thessaloniki, Biochemistry Laboratory, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
| | - Aikaterini Papagianni
- Department of Nephrology, School of Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Georgios Tsoulfas
- Department of Transplant Surgery, School of Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Asimina Fylaktou
- Department of Immunology, National Peripheral Histocompatibility Center, Hippokration General Hospital, Thessaloniki 54642, Greece
| |
Collapse
|
|
24
|
COVID-19 Infection and Response to Vaccination in Chronic Kidney Disease and Renal Transplantation: A Brief Presentation. Life (Basel) 2022; 12:life12091358. [PMID: 36143394 PMCID: PMC9505388 DOI: 10.3390/life12091358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/21/2022] [Accepted: 08/26/2022] [Indexed: 01/08/2023] Open
Abstract
Chronic kidney disease (CKD) is associated with phenotypic and functional changes in the immune system, followed by detrimental clinical consequences, such as severe infections and defective response to vaccination. Two years of the pandemic, due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have undoubtedly changed the world; however, all efforts to confront infection and provide new generation vaccines tremendously improved our understanding of the mechanisms of the immune response against infections and after vaccination. Humoral and cellular responses to vaccines, including mRNA vaccines, are apparently affected in CKD patients, as elimination of recent thymic emigrant and naïve lymphocytes and regulatory T-cells, together with contraction of T-cell repertoire and homeostatic proliferation rate, which characterized CKD patients are responsible for impaired immune activation. Successful renal transplantation will restore some of these changes, although several epigenetic changes are irreversible and even accelerated by the induction of immunosuppression. Response to vaccination is definitely impaired among both CKD and RT patients. In the present review, we analyzed the differences in immune response after vaccination between these patients and healthy individuals and depicted specific parameters, such as alterations in the immune system, predisposing to this deficient response.
Collapse
|
|
25
|
AI and Immunoinformatics. Artif Intell Med 2022. [DOI: 10.1007/978-3-030-64573-1_113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
|
|
26
|
Wang Z, Xu H, Cheng F, Zhang J, Feng Y, Liu D, Shang W, Feng G. Donor BMSC-derived small extracellular vesicles relieve acute rejection post-renal allograft through transmitting Loc108349490 to dendritic cells. Aging Cell 2021; 20:e13461. [PMID: 34499402 PMCID: PMC8520728 DOI: 10.1111/acel.13461] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 07/19/2021] [Accepted: 08/06/2021] [Indexed: 12/24/2022] Open
Abstract
Bone marrow-derived mesenchymal stem cell (BMSC)-derived small extracellular vesicles (sEVs) are potent candidates for the suppression of acute rejection post-renal allograft and have been reported to halt dendritic cells (DCs) maturation. However, whether BMSC-derived sEVs mitigate acute rejection post-renal allograft by targeting DCs is still unclear. In this study, donor BMSC-derived sEVs (sEVs) relieved the inflammatory response and suppressed mature DCs (mDCs) location in kidney grafts, and increased regulatory T (Treg) cell population in the spleens of the rats that underwent kidney allograft. In lipopolysaccharide (LPS)-stimulated immature DCs (imDCs), sEVs suppressed the maturation and migration of DCs and inactivated toll-like receptor 4 (TLR4) signaling. Compared with LPS-treated imDCs, imDCs treated with LPS+sEVs promoted CD4+ T cells differentiated toward Treg cells. Subsequently, we found that Loc108349490, a long non-coding RNA (lncRNA) abundant in sEVs, mediated the inhibitory effect of sEVs on DC maturation and migration by promoting TLR4 ubiquitination. In rats that underwent an allograft, Loc108349490 deficiency weakened the therapeutic effect of sEVs on acute rejection. The present study firstly found that sEVs alleviated acute rejection post-renal allograft by transferring lncRNA to DCs and screened out the functional lncRNA loaded in sEVs was Loc108349490.
Collapse
Affiliation(s)
- Zhi‐gang Wang
- Department of Kidney TransplantationThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Hong‐en Xu
- Precision Medicine Center of Zhengzhou UniversityAcademy of Medical SciencesZhengzhou UniversityZhengzhouChina
| | - Fu‐min Cheng
- Department of Kidney TransplantationThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Jie Zhang
- Department of Kidney TransplantationThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Yong‐hua Feng
- Department of Kidney TransplantationThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Dan‐hua Liu
- Precision Medicine Center of Zhengzhou UniversityAcademy of Medical SciencesZhengzhou UniversityZhengzhouChina
| | - Wen‐jun Shang
- Department of Kidney TransplantationThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Gui‐wen Feng
- Department of Kidney TransplantationThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| |
Collapse
|
|
27
|
Mira FS, Figueiredo C, Rodrigues L, Romãozinho C, Galvão A, Figueiredo A, Alves R. Tacrolimus Trough Intravariability in Patients Treated With the Prolonged-Release Formulation Is a Risk Factor for Acute Graft Rejection. EXP CLIN TRANSPLANT 2021; 19:910-913. [PMID: 34545776 DOI: 10.6002/ect.2021.0231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES Tacrolimus has a narrow therapeutic window, and lack of adherence to the therapeutic regimen is a main risk factor for acute graft rejection; hence, the prolonged-release formulation was created. A high intrapatient variability for tacrolimus trough levels has been associated with worse graft outcomes; therefore, we investigated the correlation between the tacrolimus variation coefficient and the development of biopsy-proven acute graft rejection in kidney transplant patients with typical maintenance immunosuppression versus the prolonged-release formulation. MATERIALS AND METHODS This was a single-center observational retrospective study that included all adult kidney transplants from deceased donors between January 2011 and December 2014 for which the transplant recipients were given maintenance therapy with tacrolimus prolonged-release formulation (Advagraf). The overall tacrolimus variation coefficient was calculated for the follow-up period from transplant until December 2019. Biopsy-proven acute graft rejection results were collected throughout follow-up. Statistical analysis was performed with SPSS software. RESULTS The study was composed of 147 patients with a mean follow-up time of 60.4 ± 15 months. The mean age of the patients was 47.5 ± 11.9 years and 67.3% were men. Of these 147 patients, 29 had at least 1 episode of acute graft rejection during follow-up. There was a significant correlation between patients with a higher tacrolimus variation coefficient and the presence of biopsy-proven acute graft rejection. Receiver operating characteristic curves were used to determine an intrapatient variability cutoff point of 28.3% for tacrolimus. Younger patients were also more likely than older patients to develop acute graft rejection in our sample. CONCLUSIONS High intrapatient variability of tacrolimus trough levels is a risk factor for acute graft rejection in kidney transplant patients.
Collapse
Affiliation(s)
- Filipe S Mira
- From the Nephrology Department, Coimbra University Hospital, and the Faculty of Medicine, Coimbra, Portugal
| | | | | | | | | | | | | |
Collapse
|
|
28
|
Roballo KCS, Gigley JP, Smith TA, Bittner GD, Bushman JS. Functional and immunological peculiarities of peripheral nerve allografts. Neural Regen Res 2021; 17:721-727. [PMID: 34472457 PMCID: PMC8530136 DOI: 10.4103/1673-5374.322445] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
This review addresses the accumulating evidence that live (not decellularized) allogeneic peripheral nerves are functionally and immunologically peculiar in comparison with many other transplanted allogeneic tissues. This is relevant because live peripheral nerve allografts are very effective at promoting recovery after segmental peripheral nerve injury via axonal regeneration and axon fusion. Understanding the immunological peculiarities of peripheral nerve allografts may also be of interest to the field of transplantation in general. Three topics are addressed: The first discusses peripheral nerve injury and the potential utility of peripheral nerve allografts for bridging segmental peripheral nerve defects via axon fusion and axon regeneration. The second reviews evidence that peripheral nerve allografts elicit a more gradual and less severe host immune response allowing for prolonged survival and function of allogeneic peripheral nerve cells and structures. Lastly, potential mechanisms that may account for the immunological differences of peripheral nerve allografts are discussed.
Collapse
Affiliation(s)
| | - Jason P Gigley
- Department of Molecular Biology, University of Wyoming, Laramie, WY, USA
| | - Tyler A Smith
- Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA
| | - George D Bittner
- Department of Neuroscience, University of Texas at Austin, Austin, TX, USA
| | | |
Collapse
|
|
29
|
Pandey P, Pande A, Kumar Devra A, Kumar Sinha V, Prasad Bhatt A. Comparative analysis of complement-dependent lymphocytotoxicity crossmatch and flow cytometry crossmatch results versus Luminex single-antigen bead-based donor-specific IgG class I antibody MFI values in live related renal transplant cases; a retrospective observation in 102 cases. J Immunoassay Immunochem 2021; 42:300-313. [PMID: 33356865 DOI: 10.1080/15321819.2020.1862865] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
The aim of this study was to compare the results of solid phase assay and cell-based assay, and explore the near-accurate DSA-MFI-cutoff value detected on solid phase assay above which the cell-based assay would show a positive result. In this retrospective study, 102 prospective renal transplant recipients were tested for the presence of donor-specific antibodies (DSAs) by cell-based assay (T-cell-CDC-AHG-XM and T-cell-IgG-FC-XM) and solid phase assay (class-I-IgG-L-SAB) with their corresponding donor. Among the 40 patients in the group first (L-SAB-DSA-MFI<1000), one case was positive in IgG-T-cell-FC-XM while T-cell-CDC-AHG-XM was negative in all the cases. In the second group having L-SAB-DSA-MFI values between 1000 and 3000, 19 cases were positive and the remaining 11 cases were negative in IgG-T-cell-FC-XM. T-cell-CDC-AHG-XM showed a negative reaction in all 30 cases. In the third group having L-SAB-DSA-MFI values between 3000 and 5000, IgG-T-cell-FC-XM was positive in 18 cases while, two were negative. T-cell-CDC-AHG-XM demonstrated a negative result in 14 cases while reaming six cases demonstrated a positive result. In the fourth group having L-SAB-DSA-MFI values >5000, all 12 cases showed a positive result in both IgG-T-cell FC-XM and T-cell-CDC-AHG-XM. Our results indicated that the L-SAB-DSA-MFI values >2215 were significantly (P < .001) correlated with positive IgG-T-cell-FC-XM while L-SAB-DSA-MFI values >4689 were significantly (P < .001) correlated with positive CDC-XM.
Collapse
Affiliation(s)
- Prashant Pandey
- Transfusion Medicine, Histocompatibility, Molecular Biology, Jaypee Hospital, Noida, (U.P), India
| | - Amit Pande
- Transfusion Medicine, Histocompatibility, Molecular Biology, Jaypee Hospital, Noida, (U.P), India
| | - Amit Kumar Devra
- Urology and Kidney Transplant, Jaypee Hospital, Noida, (U.P), India
| | - Vijay Kumar Sinha
- Nephrology and Kidney Transplant, Jaypee Hospital, Noida, (U.P), India
| | - Anil Prasad Bhatt
- Nephrology and Kidney Transplant, Jaypee Hospital, Noida, (U.P), India
| |
Collapse
|
|
30
|
Burek Kamenaric M, Ivkovic V, Kovacevic Vojtusek I, Zunec R. The Role of HLA and KIR Immunogenetics in BK Virus Infection after Kidney Transplantation. Viruses 2020; 12:v12121417. [PMID: 33317205 PMCID: PMC7763146 DOI: 10.3390/v12121417] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 12/04/2020] [Accepted: 12/08/2020] [Indexed: 12/13/2022] Open
Abstract
BK virus (BKV) is a polyomavirus with high seroprevalence in the general population with an unremarkable clinical presentation in healthy people, but a potential for causing serious complications in immunosuppressed transplanted patients. Reactivation or primary infection in kidney allograft recipients may lead to allograft dysfunction and subsequent loss. Currently, there is no widely accepted specific treatment for BKV infection and reduction of immunosuppressive therapy is the mainstay therapy. Given this and the sequential appearance of viruria-viremia-nephropathy, screening and early detection are of utmost importance. There are numerous risk factors associated with BKV infection including genetic factors, among them human leukocyte antigens (HLA) and killer cell immunoglobulin-like receptors (KIR) alleles have been shown to be the strongest so far. Identification of patients at risk for BKV infection would be useful in prevention or early action to reduce morbidity and progression to frank nephropathy. Assessment of risk involving HLA ligands and KIR genotyping of recipients in the pre-transplant or early post-transplant period might be useful in clinical practice. This review summarizes current knowledge of the association between HLA, KIR and BKV infection and potential future directions of research, which might lead to optimal utilization of these genetic markers.
Collapse
Affiliation(s)
- Marija Burek Kamenaric
- Tissue Typing Center, Clinical Department of Transfusion Medicine and Transplantation Biology, University Hospital Center Zagreb, 10 000 Zagreb, Croatia;
| | - Vanja Ivkovic
- Department of Nephrology, Hypertension, Dialysis and Transplantation, University Hospital Center Zagreb, 10 000 Zagreb, Croatia; (V.I.); (I.K.V.)
- Department of Public Health, Faculty of Health Studies, University of Rijeka, 51 000 Rijeka, Croatia
| | - Ivana Kovacevic Vojtusek
- Department of Nephrology, Hypertension, Dialysis and Transplantation, University Hospital Center Zagreb, 10 000 Zagreb, Croatia; (V.I.); (I.K.V.)
| | - Renata Zunec
- Tissue Typing Center, Clinical Department of Transfusion Medicine and Transplantation Biology, University Hospital Center Zagreb, 10 000 Zagreb, Croatia;
- Correspondence:
| |
Collapse
|
|
31
|
Iorember F, Aviles D, Bamgbola O. Impact of immediate post-transplant parenteral iron therapy on the prevalence of anemia and short-term allograft function in a cohort of pediatric and adolescent renal transplant recipients. Pediatr Transplant 2020; 24:e13787. [PMID: 32678506 DOI: 10.1111/petr.13787] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 05/14/2020] [Accepted: 06/16/2020] [Indexed: 12/29/2022]
Abstract
Anemia is common but under-diagnosed and often inadequately treated in KTX recipients. ID is the major cause of early-onset anemia. We introduced routine use of parenteral (IV) iron in patients (2-18 years) who had KTX between January 2011 and December 2015. We explored the clinical benefits of this practice by comparing the iron-treated subjects [TX] with historical controls who had KTX between 2005 and 2010. The prevalence of anemia at 6 months (early-onset) for the cohort (both the study group and controls) was 55% and for anemia at 12 months (late-onset) was 60%. Although cause-effect relationship may not be proven in a retrospective study design, there was a significant greater frequency of ID and anemia at 3 (P < .02) and 6 months (P < .04), and a reduced allograft function (eGFR < 60 mL/min/1.73 m2 ) at 12 (P = .03) and 24 months (P = .04) of KTX in the control arm. Furthermore, a greater proportion of the control arm required either ESA (P = .03) or blood transfusion (P = .04) as a rescue treatment for moderate-to-severe anemia. In conclusion, routine parenteral iron treatment was associated with a lower prevalence of early- and late-onset anemia, and a lower requirement for either ESA rescue or blood transfusion.
Collapse
Affiliation(s)
- Franca Iorember
- Division of Pediatric Nephrology, Phoenix Children's Hospital, Phoenix, Arizona, USA
| | - Diego Aviles
- Division of Pediatric Nephrology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA
| | - Oluwatoyin Bamgbola
- Division of Pediatric Nephrology, SUNY Downstate Medical Center, Brooklyn, New York, USA
| |
Collapse
|
|
32
|
Calabrese LH, Caporali R, Blank CU, Kirk AD. Modulating the wayward T cell: New horizons with immune checkpoint inhibitor treatments in autoimmunity, transplant, and cancer. J Autoimmun 2020; 115:102546. [PMID: 32980229 DOI: 10.1016/j.jaut.2020.102546] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 09/02/2020] [Accepted: 09/14/2020] [Indexed: 12/20/2022]
Abstract
The T-cell response is regulated by the balance between costimulatory and coinhibitory signals. Immune checkpoints are essential for efficient T-cell activation, but also for maintaining self-tolerance and protecting tissues from damage caused by the immune system, and for providing protective immunity. Modulating immune checkpoints can serve diametric goals, such that blocking a coinhibitory molecule can unleash anti-cancer immunity whereas stimulating the same molecule can reduce an over-reaction in autoimmune disease. The purpose of this review is to examine the regulation of T-cell costimulation and coinhibition, which is central to the processes underpinning autoimmunity, transplant rejection and immune evasion in cancer. We will focus on the immunomodulation agents that regulate these unwanted over- and under-reactions. The use of such agents has led to control of symptoms and slowing of progression in patients with rheumatoid arthritis, reduced rejection rates in transplant patients, and prolonged survival in patients with cancer. The management of immune checkpoint inhibitor treatment in certain challenging patient populations, including patients with pre-existing autoimmune conditions or transplant patients who develop cancer, as well as the management of immune-related adverse events in patients receiving antitumor therapy, is examined. Finally, the future of immune checkpoint inhibitors, including examples of emerging targets that are currently in development, as well as recent insights gained using new molecular techniques, is discussed. T-cell costimulation and coinhibition play vital roles in these diverse therapeutic areas. Targeting immune checkpoints continues to be a powerful avenue for the development of agents suitable for treating autoimmune diseases and cancers and for improving transplant outcomes. Enhanced collaboration between therapy area specialists to share learnings across disciplines will improve our understanding of the opposing effects of treatments for autoimmune disease/transplant rejection versus cancer on immune checkpoints, which has the potential to lead to improved patient outcomes.
Collapse
Affiliation(s)
| | - Roberto Caporali
- University of Milan, Department of Clinical Sciences and Community Health and Rheumatology Division, ASST Pini-CTO Hospital, Milan, Italy
| | | | - Allan D Kirk
- Department of Surgery, Duke University School of Medicine, Durham, NC, United States
| |
Collapse
|
|
33
|
Yuzefovych Y, Valdivia E, Rong S, Hack F, Rother T, Schmitz J, Bräsen JH, Wedekind D, Moers C, Wenzel N, Gueler F, Blasczyk R, Figueiredo C. Genetic Engineering of the Kidney to Permanently Silence MHC Transcripts During ex vivo Organ Perfusion. Front Immunol 2020; 11:265. [PMID: 32140158 PMCID: PMC7042208 DOI: 10.3389/fimmu.2020.00265] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 01/31/2020] [Indexed: 12/29/2022] Open
Abstract
Organ gene therapy represents a promising tool to correct diseases or improve graft survival after transplantation. Polymorphic variation of the major histocompatibility complex (MHC) antigens remains a major obstacle to long-term graft survival after transplantation. Previously, we demonstrated that MHC-silenced cells are protected against allogeneic immune responses. We also showed the feasibility to silence MHC in the lung. Here, we aimed at the genetic engineering of the kidney toward permanent silencing of MHC antigens in a rat model. We constructed a sub-normothermic ex vivo perfusion system to deliver lentiviral vectors encoding shRNAs targeting β2-microglobulin and the class II transactivator to the kidney. In addition, the vector contained the sequence for a secreted nanoluciferase. After kidney transplantation (ktx), we detected bioluminescence in the plasma and urine of recipients of an engineered kidney during the 6 weeks of post-transplant monitoring, indicating a stable transgene expression. Remarkably, transcript levels of β2-microglobulin and the class II transactivator were decreased by 70% in kidneys expressing specific shRNAs. Kidney genetic modification did not cause additional cell death compared to control kidneys after machine perfusion. Nevertheless, cytokine secretion signatures were altered during perfusion with lentiviral vectors as revealed by an increase in the secretion of IL-10, MIP-1α, MIP-2, IP-10, and EGF and a decrease in the levels of IL-12, IL-17, MCP-1, and IFN-γ. Biodistribution assays indicate that the localization of the vector was restricted to the graft. This study shows the potential to generate immunologically invisible kidneys showing great promise to support graft survival after transplantation and may contribute to reduce the burden of immunosuppression.
Collapse
Affiliation(s)
- Yuliia Yuzefovych
- Hannover Medical School, Institute of Transfusion Medicine and Transplant Engineering, Hanover, Germany
| | - Emilio Valdivia
- Hannover Medical School, Institute of Transfusion Medicine and Transplant Engineering, Hanover, Germany
| | - Song Rong
- Department of Nephrology, Hannover Medical School, Hanover, Germany
| | - Franziska Hack
- Hannover Medical School, Institute of Transfusion Medicine and Transplant Engineering, Hanover, Germany
| | - Tamina Rother
- Hannover Medical School, Institute of Transfusion Medicine and Transplant Engineering, Hanover, Germany
| | - Jessica Schmitz
- Hannover Medical School, Institute for Pathology, Hanover, Germany
| | | | - Dirk Wedekind
- Hannover Medical School, Institute for Laboratory Animal Science, Hanover, Germany
| | - Cyril Moers
- Department of Surgery-Organ Donation and Transplantation, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Nadine Wenzel
- Hannover Medical School, Institute of Transfusion Medicine and Transplant Engineering, Hanover, Germany
| | - Faikah Gueler
- Department of Nephrology, Hannover Medical School, Hanover, Germany
| | - Rainer Blasczyk
- Hannover Medical School, Institute of Transfusion Medicine and Transplant Engineering, Hanover, Germany
| | - Constanca Figueiredo
- Hannover Medical School, Institute of Transfusion Medicine and Transplant Engineering, Hanover, Germany
| |
Collapse
|
|
34
|
|