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HLA Desensitization in Solid Organ Transplantation: Anti-CD38 to Across the Immunological Barriers.

ABSTRACT: The presence of anti-human leucocyte antigen (HLA) antibodies in the potential solid organ transplant recipient's blood is one of the main barriers to access to a transplantation. The HLA sensitization is associated with longer waitlist time, antibody mediated rejection and transplant lost leading to increased recipient's morbidity and mortality. However, solid organ transplantation across the HLA immunological barriers have been reported in recipients who were highly sensitized to HLA using desensitization protocols. These desensitization regimens are focused on the reduction of circulating HLA antibodies. Despite those strategies improve rates of transplantation, it remains several limitations including persistent high rejection rate and worse long-term outcomes when compare with non-sensitized recipient population. Currently, interest is growing in the development of new desensitization approaches which, beyond targeting antibodies, would be based on the modulation of alloimmune pathways. Plasma cells appears as an interesting target given their critical role in antibody production. In the last decade, CD38-targeting immunotherapies, such as daratumumab, have been recognized as a key component in the treatment of myeloma by inducing an important plasma cell depletion. This review focuses on an emerging concept based on targeting CD38 to desensitize in the field of transplantation.

SUBMITTER: Joher N

PROVIDER: S-EPMC8173048 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Current Approaches to Desensitization in Solid Organ Transplantation.

Project description:Major advancements in the development of HLA antibody detection techniques and our understanding of the outcomes of solid organ transplant in the context of HLA antibody have occurred since the relevance of sensitization was first recognized nearly 50 years ago. Additionally, kidney paired donation programs (KPD) have become widespread, deceased donor allocation policies have changed, and several new therapeutic options have become available with promise to reduce HLA antibody. In this overview we aim to provide thoughtful guidance about when desensitization in kidney transplantation should be considered taking into account the outcomes of HLA incompatible transplantation. Novel therapeutics, desensitization endpoints, and strategies for future study will also be discussed. While most of our understanding about desensitization comes from studying kidney transplant candidates and recipients, many of the concepts discussed can be easily applied to desensitization in all of solid organ transplantation.

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Perceived barriers to medication adherence remain stable following solid organ transplantation.

Project description:Perceived barriers to adherence have previously been investigated in SOT to identify plausible intervention targets to improve adherence and transplant outcomes. Fifteen centers in CTOTC enrolled patients longitudinally. Patients >8 years completed Adolescent Scale(AMBS) at two visits at least 6 months apart in the first 17 months post-transplant while their guardians completed PMBS. Differences over time for pre-identified AMBS/PMBS factors were analyzed. Perceived barrier reporting impact on subsequent TAC levels was assessed. A total of 123 patients or their guardians completed PMBS or AMBS. Twenty-six were 6-11 years and 97 were ≥12. The final cohort consisted of kidney (66%), lung (19%), liver (8%), and heart (7%) recipients. Unadjusted analysis showed no statistically significant change in reported barriers from visit 1 (median 2.6 months, range 1.2-3.7 post-transplant) to visit 2 (median 12, range 8.9-16.5). Of 102 patients with TAC levels, 74 had a single level reported at both visits. The factor of "Disease frustration" was identified through the PMBS/AMBS questions about fatigue around medication and disease. Each point increase in "disease frustration" at visit 1 on the AMBS/PMBS doubled the odds of a lower-than-threshold TAC level at visit 2. No clear change in overall level of perceived barriers to medication adherence in the first year post-transplant was seen in pediatric SOT. However, disease frustration early post-transplant was associated with a single subtherapeutic TAC levels at 12 months. A brief screening measure may allow for early self-identification of risk.

| S-EPMC6652201 | biostudies-literature

Complement-activating donor-specific anti-HLA antibodies in solid organ transplantation: systematic review, meta-analysis, and critical appraisal.

Project description:IntroductionSeveral studies have investigated the impact of circulating complement-activating anti-human leukocyte antigen donor-specific antibodies (anti-HLA DSAs) on organ transplant outcomes. However, a critical appraisal of these studies and a demonstration of the prognostic value of complement-activating status over anti-HLA DSA mean fluorescence intensity (MFI) level are lacking.MethodsWe conducted a systematic review, meta-analysis and critical appraisal evaluating the role of complement-activating anti-HLA DSAs on allograft outcomes in different solid organ transplants. We included studies through Medline, Cochrane, Scopus, and Embase since inception of databases till May 05, 2023. We evaluated allograft loss as the primary outcome, and allograft rejection as the secondary outcome. We used the Newcastle-Ottawa Scale and funnel plots to assess risk of bias and used bias adjustment methods when appropriate. We performed multiple subgroup analyses to account for sources of heterogeneity and studied the added value of complement assays over anti-HLA DSA MFI level.ResultsIn total, 52 studies were included in the final meta-analysis (11,035 patients). Complement-activating anti-HLA DSAs were associated with an increased risk of allograft loss (HR 2.77; 95% CI 2.33-3.29, p<0.001; I²=46.2%), and allograft rejection (HR 4.98; 95% CI 2.96-8.36, p<0.01; I²=70.9%). These results remained significant after adjustment for potential sources of bias and across multiple subgroup analyses. After adjusting on pan-IgG anti-HLA DSA defined by the MFI levels, complement-activating anti-HLA DSAs were significantly and independently associated with an increased risk of allograft loss.DiscussionWe demonstrated in this systematic review, meta-analysis and critical appraisal the significant deleterious impact and the independent prognostic value of circulating complement-activating anti-HLA DSAs on solid organ transplant risk of allograft loss and rejection.

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Computational Approaches to Facilitate Epitope-Based HLA Matching in Solid Organ Transplantation.

Project description:Epitope-based HLA matching has been emerged over the last few years as an improved method for HLA matching in solid organ transplantation. The epitope-based matching concept has been incorporated in both the PIRCHE-II and the HLAMatchmaker algorithm to find the most suitable donor for a recipient. For these algorithms, high-resolution HLA genotype data of both donor and recipient is required. Since high-resolution HLA genotype data is often not available, we developed a computational method which allows epitope-based HLA matching from serological split level HLA typing relying on HLA haplotype frequencies. To validate this method, we simulated a donor-recipient population for which PIRCHE-II and eplet values were calculated when using both high-resolution HLA genotype data and serological split level HLA typing. The majority of the serological split level HLA-determined ln(PIRCHE-II)/ln(eplet) values did not or only slightly deviate from the reference group of high-resolution HLA-determined ln(PIRCHE-II)/ln(eplet) values. This deviation was slightly increased when HLA-C or HLA-DQ was omitted from the input and was substantially decreased when using two-field resolution HLA genotype data of the recipient and serological split level HLA typing of the donor. Thus, our data suggest that our computational approach is a powerful tool to estimate PIRCHE-II/eplet values when high-resolution HLA genotype data is not available.

| S-EPMC5329668 | biostudies-literature

Biological Characteristics of HLA-G and Its Role in Solid Organ Transplantation.

Project description:Organ transplantation is a lifesaving option for patients with advanced diseases. Rejection is regarded as one of the most severe risk factors post-transplantation. A molecule that contributes to immune tolerance and resisting rejection is human leukocyte antigen (HLA)-G, which belongs to the non-classical major histocompatibility complex class (MHC) I family. HLA-G was originally found to play a role during pregnancy to maintain immune tolerance between mother and child. It is expressed in the placenta and detected in several body fluids as soluble factor as well as different membrane isoforms on cells. Recent findings on HLA-G show that it can also play multifaceted roles during transplantation. This review will explain the general characteristics and biological function of HLA-G and summarize the views supporting the tolerogenic and other roles of HLA-G to better understand its role in solid organ transplantation (SOT) and its complications. Finally, we will discuss potential future research on the role of HLA-G in prevention, diagnosis, and treatment in SOT.

| S-EPMC9234285 | biostudies-literature

Desensitization: Overcoming the Immunologic Barriers to Transplantation.

Project description:HLA (Human Leucocyte Antigen) sensitization is a significant barrier to successful kidney transplantation. It often translates into difficult crossmatch before transplant and increased risk of acute and chronic antibody mediated rejection after transplant. Over the last decade, several immunomodulatory therapies have emerged allowing for increased access to kidney transplantation for the immunologically disadvantaged group of HLA sensitized end stage kidney disease patients. These include IgG inactivating agents, anti-cytokine antibodies, costimulatory molecule blockers, complement inhibitors, and agents targeting plasma cells. In this review, we discuss currently available agents for desensitization and provide a brief analysis of data on novel biologics, which will likely improve desensitization outcomes, and have potential implications in treatment of antibody mediated rejection.

| S-EPMC5239985 | biostudies-literature

Perceived barriers to medication adherence in pediatric and adolescent solid organ transplantation.

Project description:Comparisons of perceived barriers to adherence in pediatric and adolescent SOT have not been systematically conducted despite association between medication non-adherence and poor outcome. Fifteen centers in CTOT-C enrolled patients in a cross-sectional study. Subjects' guardians completed the PMBS and subjects over eight completed the Adolescent Scale (AMBS). Association of three identified PMBS factors and subject age was assessed. Secondary analyses assessed associations between PMBS, AMBS, and patient demographics. Three hundred sixty-eight subjects or their guardians completed PMBS or AMBS. A total of 107 subjects were 6-11 yr; 261 were ≥12. Unadjusted and propensity-adjusted analyses indicated higher perceived barriers in guardians of adolescents as compared to guardians of pre-adolescents medication scheduling and frustration domains regardless of organ (p < 0.05). PMBS and AMBS comparisons revealed that guardians reported fewer ingestion issues than patients (p = 0.018), and differences appeared more pronounced within younger responders for scheduling (p = 0.025) and frustration (p = 0.019). Screening revealed guardians of older patients report increased perceived barriers to adherence independent of socioeconomic status. Guardians of adolescents reported fewer perceived barriers to ingestion/side effects than patients themselves, particularly in pre-adolescents (8-11 yr). Brief screening measures to assess perceived barriers should be further studied in adherence improvement programs.

| S-EPMC6422022 | biostudies-literature

HLA and Risk of Diffuse Large B cell Lymphoma After Solid Organ Transplantation.

Project description:BACKGROUND:Solid organ transplant recipients have heightened risk for diffuse large B cell lymphoma (DLBCL). The role of donor-recipient HLA mismatch and recipient HLA type on DLBCL risk are not well established. METHODS:We examined 172 231 kidney, heart, pancreas, and lung recipients transplanted in the United States between 1987 and 2010, including 902 with DLBCL. Incidence rate ratios (IRRs) were calculated using Poisson regression for DLBCL risk in relation to HLA mismatch, types, and zygosity, adjusting for sex, age, race/ethnicity, year, organ, and transplant number. RESULTS:Compared with recipients who had 2 HLA-DR mismatches, those with zero or 1 mismatch had reduced DLBCL risk, (zero: IRR, 0.76, 95% confidence interval [95% CI], 0.61-0.95; one: IRR, 0.83; 95% CI, 0.69-1.00). In stratified analyses, recipients matched at either HLA-A, -B, or -DR had a significantly reduced risk of late-onset (>2 years after transplantation), but not early-onset DLBCL, and there was a trend for decreasing risk with decreasing mismatch across all 3 loci (P = 0.0003). Several individual recipient HLA-A, -B, -C, -DR, and -DQ antigens were also associated with DLBCL risk, including DR13 (IRR, 0.74; 95% CI, 0.57-0.93) and B38 (IRR, 1.48; 95% CI, 1.10-1.93), confirming prior findings that these 2 antigens are associated with risk of infection-associated cancers. CONCLUSIONS:In conclusion, variation in HLA is related to susceptibility to DLBCL, perhaps reflecting intensity of immunosuppression, control of Epstein-Barr virus infection among transplant recipients or chronic immune stimulation.

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Immunological Prediction of Cytomegalovirus (CMV) Replication Risk in Solid Organ Transplantation Recipients: Approaches for Regulating the Targeted Anti-CMV Prevention Strategies.

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| S-EPMC5620383 | biostudies-literature

Fc? Receptors in Solid Organ Transplantation.

Project description:In the current era, one of the major factors limiting graft survival is chronic antibody-mediated rejection (ABMR), whilst patient survival is impacted by the effects of immunosuppression on susceptibility to infection, malignancy and atherosclerosis. IgG antibodies play a role in all of these processes, and many of their cellular effects are mediated by Fc gamma receptors (Fc?Rs). These surface receptors are expressed by most immune cells, including B cells, natural killer cells, dendritic cells and macrophages. Genetic variation in FCGR genes is likely to affect susceptibility to ABMR and to modulate the physiological functions of IgG. In this review, we discuss the potential role played by Fc?Rs in determining outcomes in solid organ transplantation, and how genetic polymorphisms in these receptors may contribute to variations in transplant outcome.

| S-EPMC5107199 | biostudies-literature

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