Donor-specific Antibody Formation Research Articles

Marginal Zone B Cells Are Necessary for the Formation of Anti-donor IgG After Allogeneic Sensitization.

The formation of anti-major histocompatibility complex (MHC) antibodies is a significant barrier for many patients awaiting organ transplantation. Patients with preformed anti-MHC antibodies have limited options for suitable donors, and the formation of donor-specific anti-MHC antibodies after transplantation is a harbinger of graft rejection. Despite the recognized importance of anti-MHC antibodies, the mechanisms responsible for the differentiation of B cells after exposure to allogeneic antigens are poorly understood. To evaluate the differentiation of B cells in response to allogeneic antigen, we used a model of H-2 b C57Bl/6 sensitization with H-2 d antigen. We used a class I MHC tetramer-based approach to identify allogeneic B cells and flow cytometric crossmatch to identify allogeneic IgM and IgG. We found that although the formation of anti-H-2 d IgG was robust, few class-switched B cells and germinal center B cells were formed. Antigen-specific B cells did not express classical memory B-cell markers after sensitization but had an IgM + CD21 + marginal zone B-cell phenotype. The frequency of marginal zone B cells increased after sensitization. Depletion of marginal zone B cells before sensitization or skin grafting resulted in a significant diminution of anti-H-2 d IgG and fewer germinal center B cells. Adoptive transfer experiments revealed that marginal zone B cells more efficiently differentiated into germinal center B cells and anti-donor IgG-producing cells than follicular B cells. These results demonstrate an important role for marginal zone B cells as a reservoir of alloreactive B cells that are activated by allogeneic antigens.

Impact of HLA Eplet Mismatch on De Novo Donor Specific Antibody Formation After Kidney Transplantation

HLA eplet mismatching is an alternative approach to assess the risk of developing de novo donor-specific antibodies (dnDSA) in kidney transplantation. This strategy may offer more precise risk stratification than conventional approaches. This study aimed to find the association between HLA eplet mismatches and dnDSA formation in Thai kidney transplant recipients. A retrospective cohort study of kidney transplant recipients transplanted between 2000 and 2021 at Ramathibodi Hospital was performed. Recipients with pretransplant panel reactive antibody >0% or without DSA testing post-transplant were excluded. One hundred fifty recipients were included in the final study. High-resolution HLA typing was imputed by the HaploStat application. HLA eplet mismatch analysis was conducted using HLAMatchmaker. The association between the number of eplet mismatches and the risk of dnDSA formation was assessed by Cox regression analysis. Of 150 recipients, 43 were dnDSA-positive, and 107 were dnDSA-negative patients. Compared with the dnDSA-negative group, patients with class II dnDSA had significantly more HLA-DR/DQ antibody (Ab)-verified eplet mismatches (6 [IQR 4-8] vs 4 [IQR 1-7], P = .045). The receiver operating characteristics analysis showed that the HLA-DQ Ab-verified eplet mismatches ≥2 were the best predictive of HLA class II dnDSA development. The number of HLA-DQ Ab-verified eplet mismatches ≥2 had the highest hazard rate of HLA class II dnDSA occurrence (adjusted HR, 3.74; 95%CI, 1.24-11.24, P = .019). HLA-DQ Ab-verified eplet mismatches are significantly associated with class II dnDSA development. Our data supports the utility of HLA eplet mismatching for donor-recipient risk assessment.

Trajectories of postoperative serum troponin concentrations following pediatric heart transplantation

IntroductionTroponin is a readily measured serum biomarker of myocardial injury and death, but has not been well studied after pediatric heart transplants. The objective of this analysis is to describe the distribution and clinical determinants of serum troponin measured in the first week after pediatric heart transplantation. MethodsWe included all patients who underwent heart transplantation at Seattle Children’s Hospital between January 1, 2012 and December 31, 2016. During this period, serum Troponin-I (TnI) was measured daily in the first week after heart transplant. We described the distribution of serum TnT collected in this period. We examined the relationship between peak TnI with known pre- peri-operative risk factors for myocardial injury including etiology of heart failure, ischemia time, and donor to recipient characteristics. Logistic regression models were used to test the association between peak TnI with incidence of death or rejection and formation of donor specific antibodies within 1 year. Adjusted models included age, HF etiology, crossmatch status, and panel reactive antibodies. ResultsDuring the study period, 86 transplants were performed on 83 unique individuals. Serum TnI peaked at a median of 0.9 days after transplantation. In adjusted models, higher peak TnI was associated with death and/or rejection within 1-year post-transplant (Odds Ratio [95% confidence interval]: 1.10 [1.02, 1.19]). Higher peak TnI was not associated with de-novo DSA formation in adjusted models (OR [95%CI]: 1.01 [0.94, 1.09]). Post-transplant length of stay in the intensive care unit was positively correlated with peak TnI (r=0.36, p<0.001). ConclusionsThis study provides a description of serum TnI in the first week after pediatric heart transplant; a population for whom existing data is sparse. Post-transplant TnI reflects pre- and peri-operative factors such as ischemia time. This suggests TnI may have utility as a readily measurable biomarker of transplant-related myocardial injury. Our results serve as a basis to test the prognostic significance of higher post-transplant TnI in future studies.

Early progression of chronic histologic lesions in kidney transplant biopsies is not associated with HLA histocompatibility.

Early progression of chronic histologic lesions in kidney allografts represents the main finding in graft attrition. The objective of this retrospective cohort study was to elucidate whether HLA histocompatibility is associated with progression of chronic histologic lesions in the first year post-transplant. Established associations of de novo donor-specific antibody (dnDSA) formation with HLA mismatch and microvascular inflammation (MVI) were calculated to allow for comparability with other study cohorts. We included 117 adult kidney transplant recipients, transplanted between 2016 and 2020 from predominantly deceased donors, who had surveillance biopsies at 3 and 12 months. Histologic lesion scores were assessed according to the Banff classification. HLA mismatch scores [i.e. eplet, predicted indirectly recognizable HLA-epitopes algorithm (PIRCHE-II), HLA epitope mismatch algorithm (HLA-EMMA), HLA whole antigen A/B/DR] were calculated for all transplant pairs. Formation of dnDSAs was quantified by single antigen beads. More than one-third of patients exhibited a progression of chronic lesion scores by at least one Banff grade in tubular atrophy (ct), interstitial fibrosis (ci), arteriolar hyalinosis (ah) and inflammation in the area of interstitial fibrosis and tubular atrophy (i-IFTA) from the 3- to the 12-month biopsy. Multivariable proportional odds logistic regression models revealed no association of HLA mismatch scores with progression of histologic lesions, except for ah and especially HLA-EMMA DRB1 [odds ratio (OR)=1.10, 95% confidence interval (CI) 1.03-1.18]. Furthermore, the established associations of dnDSA formation with HLA mismatch and MVI (OR=5.31, 95% CI 1.19-22.57) could be confirmed in our cohort. These data support the association of HLA mismatch and alloimmune response, while suggesting that other factors contribute to early progression of chronic histologic lesions.

Comparative analysis of Basiliximab and Alemtuzumab induction therapies in blood type A2-to-B kidney transplantation: Impact on kidney function and de novo donor-specific HLA antibodies

PurposeBlood group B kidney transplant candidates have lower transplantation rates and longer waiting times compared to other blood groups. Kidney transplantation from blood group A2-to-B has offered a solution for these patients. This study aimed to investigate the impact of Basiliximab and Alemtuzumab induction therapies on kidney function and de novo donor-specific antibodies (DSA) in blood type A2-to-B kidney transplant recipients within the first 12 months of post-transplant. MethodsA retrospective analysis was conducted on 110 consecutive A2-to-B kidney transplant recipients between January 2015 and December 2022. Of these, 46 (41.8%) received Basiliximab, while 64 (58.2%) received Alemtuzumab as induction therapy. Demographics and comorbidities data were collected and compared between the two groups. Serum samples collected at 4- and 12-month intervals post-transplant were used to assess the presence of de novo DSA. Kidney allograft function was evaluated by monitoring serum creatinine levels and assessing Creatinine Clearance based on 24-h urine collection at various time points. ResultsDuring the follow-up period, 20.00% of patients who received Alemtuzumab developed de novo DSA, whereas none of the patients induced with Basiliximab developed de novo DSA (p = 0.038). Recipients who received Basiliximab were older (mean age = 72.00) and received higher Kidney Donor Profile Index (KDPI) kidneys (mean = 75) compared to those induced with Alemtuzumab (mean age = 58.00, mean KDPI = 49) (p < 0.001), with no significant difference observed in the last follow-up creatinine clearance or creatinine levels between the two groups (p = 0.28). ConclusionThe use of Basiliximab as induction immunosuppression in A2-to-B kidney transplant recipients is associated with a lower incidence of de novo HLA DSA formation without significant differences in overall renal function compared to Alemtuzumab.

Belatacept with time-limited tacrolimus coimmunosuppression modifies the 3-year risk of eplet mismatch in kidney transplantation

Solid organ transplant donor-recipient eplet mismatch has been correlated with donor-specific antibody (DSA) formation, antibody-mediated rejection, and overall rejection rates. However, studies have been predominantly in patients on tacrolimus-based immunosuppression regimens and have not fully explored differences in ethnically and racially diverse populations. Evidence indicates that patients on belatacept have lower rates of DSA formation, suggesting mediation of the immunogenicity of mismatched human leukocyte antigen polymorphisms. We performed a retrospective, single-center analysis of class II eplet disparity in a cohort of kidney transplant recipients treated using belatacept with tacrolimus induction (Bela/TacTL) or tacrolimus regimens between 2016 and 2019. Bela/TacTL (n = 294) and tacrolimus (n = 294) cohorts were propensity score-matched with standardized difference <0.15. Single-molecule eplet risk level was associated with immune event rates for both groups. In Cox regression analysis stratified by eplet risk level, Bela/TacTL immunosuppression was associated with a decreased rate of DSA (hazard ratio [HR] = 0.4), antibody-mediated rejection (HR = 0.2), and rejection (HR = 0.45). In the low-risk group, cumulative graft failure was lower for patients on Bela/TacTL (P < .02). Analysis of eplet mismatch burden may be a useful adjunct in identifying high-risk populations with increased immunosuppression requirements and should encourage the design of allocation rules to incentivize lower-risk pairings without negatively impacting equity in access.

P121 Correlation of HLA epitope mismatches with de novo donor-specific antibody formation in renal transplant recipients – A comparison of snowflake to HLAMatchmaker and PIRCHE scores

P121 Correlation of HLA epitope mismatches with de novo donor-specific antibody formation in renal transplant recipients – A comparison of snowflake to HLAMatchmaker and PIRCHE scores

Analysis of null deletion polymorphism of glutathione S-transferase theta (GSTT-1), associated with anti-GSTT-1 antibodies development in transplantation.

Glutathione S-transferase theta 1 (GSTT1) is an enzyme involved in phase II biotransformation processes and a member of a multigene family of detoxifying and clearing reactive oxygen species. GSTT1 is polymorphic like other biotransforming enzymes, allowing variability in hepatic conjugation processes. Immunological recognition of the GSTT1 alloantigen, as evidenced by donor-specific antibodies formation, has previously been observed in recipients lacking GSTT1 protein (called GSTT1-, GSTT*0, null phenotype or homozygous for the GSTT1 deletion) who receive liver or kidney transplants from GSTT1+ donors and is a risk factor for the development of de novo hepatitis following liver transplants from a GSTT1 expressing donor. Antibodies against GSTT1 are demonstrated in patients who are GSTT1 null and received a transplant from a GSTT1+ donor. Understanding the local population frequency of the GSTT1 deletion is of value in understanding the potential clinical risk of developing post-transplant complications, which can be attributed to the nonexpression of GSTT1. A population of 173 healthy donors of the Murcia Region in Southeast Spain was evaluated for a null allele of GSTT1 (n=173). DNA was extracted, and GSTT-1 null allele detection was performed by real-time polymerase chain reaction. The frequency of the null GSTT1 genotype (nonexpression or deletion of the homozygous polymorphism of the GSTT1 protein) was 17.9% (n=31 null allele GSTT1/173 total individuals). Our data suggest that the frequency of null GSTT1 mutations in our population in Southeast Spain is 17.9%, lower than in other Caucasoid populations. This would convert our recipient population into more susceptible to nonlocal potential organ donors and less susceptible to local donors. All recipients bearing this GSTT1 deletion homozygous would be without the protein and triggering an alloantigen in the case of transplantation with a donor without deletion.

Evaluation of the relationship between de-novo DSA development and CXCR5+PD-1+CD8+ T cells and PD-1/PD-L1 mRNA expression in kidney transplant recipients.

The relationship between the Follicular Cytotoxic T cell subgroup and expression levels of PD1/PD-L1 genes and the development of donor specific antibody (DSA) is unknown. In this study, we aimed to examine CD8+CXCR5+PD-1+ follicular cytotoxic T cell levels and expression levels of PD1/PD-L1 genes in peripheral blood lymphocytes in de-novo DSA positive and negative kidney transplant recipients (KTR). In our study, expression of PD-1/ PD-L1 genes by Real-Time Quantitative PCR method and CD8+CXCR5+PD-1+ T cell expression levels by flow cytometric method were obtained from peripheral blood samples. 63 participants were included in the study (de-novo DSA positive recipients (n=22, group 1), de-novo DSA negative recipients (n=20, group 2) and healthy control (n=21, group 3). All patients had negative PRA before kidney transplantation. Expression (%) levels of target cells were evaluated by flow cytometry method. IBM SPSS Statistics for Windows Version 22 and R.3.3.2 software were used to evaluate the data. The demographic data of the groups were similar. PD-1 mRNA expression was higher in de-novo DSA positive KTR than negative (respectively, 1.03±.29/.82±.15, p: .001). CD8+CXCR5+PD-1+ T cell expression levels were found to be higher in the de-novo DSA positive group than in the negative group and similar to the healthy group (respectively, 3.06±1.98/.52±.40, p:.001, 3.06±1.98/2.78±.59, p:.62). The percentage of CD8+CXCR5+PD-1+ expressing T cells was significantly lower in the HLA-Class II+ group than other groups (HLA CI/II/ I+II, respectively, 3.63±2.72/1.65±.50/3.68±1.67, p: .04). In our study, a significant relationship was found between DSA formation and PD-1 mRNA level and CD8+CXCR5+PD-1+ follicular cytotoxic T cell in KTR.

Association of positive pre-transplant angiotensin II type 1 receptor antibodies with clinical outcomes in lung transplant recipients

IntroductionAutoantibodies against the angiotensin II type 1 receptor (AT1R-Ab) have been previously associated with de novo donor-specific antibody (DSA) formation in lung transplantation. However, data regarding the clinical significance of AT1R-Ab in long-term graft function after lung transplantation are lacking. MethodsSeventy-one patients who underwent lung transplantation between July 2016 and January 2020 were enrolled in this study. We examined the relationship between pre-transplant AT1R-Ab levels and graft function, clinical outcomes, and human leukocyte antigen (HLA) DSA levels during the first 3 years post-transplantation. ResultsSeventeen (23.9%) patients were AT1R-Ab-positive, and 54 (76.1%) were AT1R-Ab-negative. The median antibody value of the AT1R-Ab-positive group was 18 [18–22.5] U/mL, while that of the AT1R-Ab-negative group was 5.1 [3.5–8.0] U/mL (p < 0.001). There was no significant difference in the median acute cellular rejection (ACR) scores between the two groups (median [interquartile range] 1 [0.8–3] vs. 0.7 [0–1]; p = 0.145). However, there was a significant difference in the distribution of the ACR scores between the two groups (p = 0.015). Most (41.2%) patients in the pre-transplant AT1R-positive group scored above 1. The incidence of de novo DSA was also higher in AT1R-Ab-positive than in AT1R-Ab-negative patients (52.9% vs. 20.4%, p = 0.009). The incidence of chronic lung allograft dysfunction (CLAD) within 3 years was significantly higher in AT1R-Ab-positive than in AT1R-Ab-negative patients (58.3% vs. 11.8%; p < 0.001). In the multivariate Cox regression analysis, AT1R-Ab positivity (hazard ratio, 9.46; 95% confidence interval, 2.89–30.94; p < 0.001) was significantly associated with early CLAD. Furthermore, Kaplan-Meier analysis showed that AT1R-Ab-positive patients had a shorter survival time (χ2 = 39.62, p < 0.001). ConclusionHigh AT1R-Ab levels in the pre-transplant serum of lung recipients were associated with the development of de novo HLA-DSA, ACR, early CLAD, and short survival.

Excellent efficacy and beneficial safety during observational 5-year follow-up of rapid steroid withdrawal after renal transplantation (Harmony FU study).

We previously reported excellent efficacy and improved safety aspects of rapid steroid withdrawal (RSWD) in the randomized controlled 1-year "Harmony" trial with 587 predominantly deceased-donor kidney transplant recipients randomized either to basiliximab or rabbit antithymocyte globulin induction therapy and compared with standard immunosuppressive therapy consisting of basiliximab, low tacrolimus once daily, mycophenolate mofetil and corticosteroids. The 5-year post-trial follow-up (FU) data were obtained in an observational manner at a 3- and a 5-year visit only for those Harmony patients who consented to participate and covered clinical events that occurred from the second year onwards. Biopsy-proven acute rejection and death-censored graft loss rates remained low and independent of RSWD. Rapid steroid withdrawal was an independent positive factor for patient survival (adjusted hazard ratio 0.554, 95% confidence interval 0.314-0.976; P=.041).The reduced incidence of post-transplantation diabetes mellitus in RSWD patients during the original 1-year study period was not compensated by later incidences during FU. Incidences of other important outcome parameters such as opportunistic infections, malignancies, cardiovascular morbidity/risk factors, donor-specific antibody formation or kidney function did not differ during FU period. With all the limitations of a post-trial FU study, the Harmony FU data confirm excellent efficacy and beneficial safety aspects of RSWD under modern immunosuppressive therapy over the course of 5 years after kidney transplantation in an immunologically low-risk, elderly population of Caucasian kidney transplant recipients. Trial registration: Clinical trial registration number: Investigator Initiated Trial (NCT00724022, FU study DRKS00005786).

#3973 EXCELLENT EFFICACY AND BENEFICIAL SAFETY DURING FIVE YEAR FOLLOW-UP OF RAPID STEROID WITHDRAWAL AFTER RENAL TRANSPLANTATION (HARMONY STUDY)

Abstract Background and Aims We previously reported excellent efficacy and improved safety aspects of rapid steroid withdrawal in the randomized controlled one year “Harmony” trial with 587 predominantly deceased-donor kidney transplant recipients randomized either to basiliximab or rabbit antithymocyte globulin induction therapy and compared to standard immunosuppressive therapy consisting of basiliximab, low tacrolimus once daily, mycophenolate mofetil, and corticosteroids. The five-year post-trial follow-up (FU) data reported here were obtained in an observational manner to evaluate, how these excellent short-term surrogate parameters will translate into hard long-term outcome parameters like patient death/graft loss. Method The five-year post-trial follow-up data were obtained in an observational manner at a three and a five-year visit for patients who consented to participate and covered clinical events that occurred from the second year onwards. Results Biopsy-proven acute rejection and death-censored graft loss rates remained low and independent of rapid steroid withdrawal (see Figure 1). Rapid steroid withdrawal was an independent positive factor for patient survival (adjusted hazard ratio 0.554, 95 % confidence interval 0.314 to 0.976; p = 0.041, see Table 1). The reduced incidence of post-transplantation diabetes mellitus in rapid steroid withdrawal patients during the original one-year study period was not compensated by later incidences during follow-up. Incidences of other important outcome parameters such as opportunistic infections, malignancies, cardiovascular morbidity/risk factors, donor specific antibody formation, or kidney function did not differ during follow-up period. Conclusion The Harmony follow-up trial confirms excellent efficacy and beneficial safety aspects of rapid steroid withdrawal under modern immunosuppressive therapy demonstrating for the first time increased patient survival in an immunologically low-risk, elderly population of Caucasian kidney transplant recipients.

Memory T follicular helper cells drive donor-specific antibodies independent of memory B cells and primary germinal center and alloantibody formation

Human leukocyte antigen antibodies are important immunologic mediators of renal allograft loss and are difficult to control. The inability to permanently eliminate donor-specific antibodies (DSA) is partly due to an incomplete understanding of the cellular mechanisms driving alloantibody formation, recurrence, and maintenance. Memory T follicular helper (mTfh) cells rapidly interact with memory B cells upon antigen re-exposure for anamnestic humoral responses, but little is known about Tfh memory in transplantation. We hypothesized that alloreactive mTfh cells form after transplantation and play a critical role in DSA formation following alloantigen re-encounter. To test this hypothesis, we utilized murine skin allograft models to identify and characterize Tfh memory and interrogate its ability to mediate alloantibody responses. We identified alloreactive Tfh memory as a mediator of accelerated humoral alloresponses independent of memory B cells and primary germinal center, or DSA, formation. Furthermore, we demonstrate that mTfh-driven alloantibody formation is susceptible to CD28 costimulation blockade. These findings provide novel insight into a pathologic role for memory Tfh in alloantibody responses and strongly support shifting therapeutic focus from the singular targeting of B cell lineage cells and alloantibodies themselves to multimodal strategies that include inhibition of mTfh cells to treat DSA.

Extracorporeal Photopheresis Suppresses Transplant Fibrosis by Inducing Decorin Expression in Alveolar Macrophages.

Extracorporeal Photopheresis Suppresses Transplant Fibrosis by Inducing Decorin Expression in Alveolar Macrophages.

Genetic Polymorphisms in Follicular Helper T Cell–Related Molecules Predispose Patients to De Novo Donor-Specific Antibody Formation After Kidney Transplantation

Risk prediction of de novo donor-specific antibody (dnDSA) formation is crucial for understanding the long-term prognostic impact of kidney transplantation (KT). Recently, follicular helper T (Tfh) cells, a subtype of CD4+ T cells, have been reported to play an important role in dnDSA formation after solid organ transplantation. Given the growing recognition of the importance of Tfh cells in generating a strong humoral immune response, we examined whether polymorphisms in Tfh cell-related molecules were associated with dnDSA formation after KT. Eighty-three patients who underwent living-donor KT between January 2013 and February 2020 at Hiroshima University Hospital were included in the study. Six Tfh cell-related molecules (BCL6, CXCR5, CXCL13, ICOS, CD40L, and IL21) that are important for Tfh cell differentiation and maturation in secondary lymphoid tissues were investigated. CTLA4, which is important for Tfh-cell activation, was also investigated. Single nucleotide polymorphisms (SNPs) in the genes for these molecules were detected using Taq Man SNP genotyping and evaluated for their association with dnDSA formation after KT. Of the 83 KT recipients, 8 developed dnDSAs during the observation period. No statistically significant differences were observed in the baseline characteristics between patients with and without dnDSA formation, except for donor age. Among the 7 Tfh cell-related molecules, the incidence of dnDSA formation was associated with CXCR5 and CTLA4 SNPs. Furthermore, combining these 2 SNPs enabled more significant stratification of dnDSA formation. Our findings indicate that genetic polymorphisms in Tfh cell-related molecules are predisposing factors for dnDSA formation after KT.

Research Highlights.

Research Highlights.

Extended genomic HLA typing identifies previously unrecognized mismatches in living kidney transplantation.

Antibody mediated rejection (ABMR) is the most common cause of long-term allograft loss in kidney transplantation (KT). Therefore, a low human leukocyte antigen (HLA) mismatch (MM) load is favorable for KT outcomes. Hitherto, serological or low-resolution molecular HLA typing have been adapted in parallel. Here, we aimed to identify previously missed HLA mismatches and corresponding antibodies by high resolution HLA genotyping in a living-donor KT cohort. 103 donor/recipient pairs transplanted at the University of Leipzig Medical Center between 1998 and 2018 were re-typed using next generation sequencing (NGS) of the HLA loci -A, -B, -C, -DRB1, -DRB345, -DQA1, -DQB1, -DPA1, and -DPB1. Based on these data, we compiled HLA MM counts for each pair and comparatively evaluated genomic HLA-typing with pre-transplant obtained serological/low-resolution HLA (=one-field) typing results. NGS HLA typing (=two-field) data was further used for reclassification of de novo HLA antibodies as "donor-specific". By two-field HLA re-typing, we were able to identify additional MM in 64.1% (n=66) of cases for HLA loci -A, -B, -C, -DRB1 and -DQB1 that were not observed by one-field HLA typing. In patients with biopsy proven ABMR, two-field calculated MM count was significantly higher than by one-field HLA typing. For additional typed HLA loci -DRB345, -DQA1, -DPA1, and -DPB1 we observed 2, 26, 3, and 23 MM, respectively. In total, 37.3% (69/185) of de novo donor specific antibodies (DSA) formation was directed against these loci (DRB345 ➔ n=33, DQA1 ➔ n=33, DPA1 ➔ n=1, DPB1 ➔ n=10). Our results indicate that two-field HLA typing is feasible and provides significantly more sensitive HLA MM recognition in living-donor KT. Furthermore, accurate HLA typing plays an important role in graft management as it can improve discrimination between donor and non-donor HLA directed cellular and humoral alloreactivity in the long range. The inclusion of additional HLA loci against which antibodies can be readily detected, HLA-DRB345, -DQA1, -DQB1, -DPA1, and -DPB1, will allow a more precise virtual crossmatch and better prediction of potential DSA. Furthermore, in living KT, two-field HLA typing could contribute to the selection of the immunologically most suitable donors.

Donor and recipient human leukocyte antigen-G polymorphisms modulate the risk of adverse immunologic events following lung transplantation

The long-term benefits of lung transplantation (LTx) are limited by pathogenic alloimmune responses that drive injury, inflammation, and chronic dysfunction. Human leukocyte antigen-G (HLA-G) plays a key role in the modulation of these pathways. This study assesses the impact of the HLA-G genotype on immunologic risk and survival following LTx.This retrospective cohort study included 289 bilateral LTx. Recipient and donor HLA-G genotypes were analyzed to identify associations with de novo donor-specific antibodies, acute rejection, chronic lung allograft dysfunction, and allograft survival. We further assessed these associations, both individually and in paired analysis, based on a grouped haplotype classification of HLA-G expression.Donor HLA-G single nucleotide polymorphisms were associated with allograft injury, the onset of chronic lung allograft dysfunction following injury, and allograft survival. Recipient HLA-G single nucleotide polymorphisms were associated with allograft injury, cellular rejection, and donor-specific antibody formation. “Low HLA-G expression” donor haplotypes were associated with impaired allograft survival, as were “low HLA-G expression” donor-recipient haplotype pairs.This study provides compelling evidence for the role of HLA-G in modulating immunologic risk after LTx. Our results highlight the importance of both donor and recipient HLA-G genotypes on the overall risk profile and underscore the lasting influence of donor genotype on lung transplant outcomes.

Reduction in Maintenance Immunosuppression in Kidney Transplant Recipients With Stable Donor-Derived Cell-Free DNA Measurements: A Case Series

Personalization of maintenance immunosuppression in kidney transplant recipients has long remained a goal in the transplant community. The recent addition of donor-derived cell-free DNA assays to detect allograft rejection and monitor allograft health may permit for reductions in maintenance immunosuppression in recipients with stable levels. Herein, we described 5 patients with stable donor-derived cell-free DNA levels who underwent reduction in maintenance immunosuppression without precipitation of clinical rejection, proteinuria, or de novo donor specific antibody formation.

HLA antigen and HLA eplet mismatches - important factors for developing donor-specific antibodies after kidney transplantation

Kidney donor-recipient mismatches (MM) in human leukocyte antigen (HLA) system can have the impact on graft survival as de novo formation of donor-specific HLA antibodies (DSA) post-transplant can increase the risk of acute and chronic rejections. Eplets, the smallest functional units of epitopes, are in recent years also being considered in recipient-donor matching. We have retrospectively analysed the relationship between MM at HLA-A, -B, -DRB1 and -DQB1 loci and the development of DSA in 47 kidney transplant recipients that were negative for the presence of HLA antibodies pre-transplant. A total of 19 patients (40%) developed DSA (DSA+) post-transplant, revealing sensitization to HLA class II MM antigens as the most prevalent (84% of DSA+ patients). MM at all HLA loci contributed to the development of HLA locus-specific antibodies, with the prevalence of HLA-DQ sensitization, as 41% of recipients with HLA-DQ MM developed DSA. HLAMatchmaker analysis for HLA-DR/DQ total eplet MM showed statistically significant difference between DSA- (N=33) and DSA+ recipients (N=14) for a total number of eplet MM (300 in DSA- vs 248 in DSA+; P=0.0004). These results emphasize the importance of HLA Class II matching in kidney transplantation.