Predicted Indirectly Recognizable HLA Epitopes Research Articles

P477 PIRCHE (PREDICTED INDIRECTLY RECOGNIZABLE HLA EPITOPES) ALGORITHM AS A POSSIBLE PREDICTOR OF AMR (ANTIBODY MEDIATED REJECTION) FOLLOWING HEART TRANSPLANT, FROM LAB EXPERIENCE TO CLINICAL PRACTICE: A CASE REPORT

Abstract PIRCHE–II is an algorithm used to estimate the risk for developing alloreactivity towards HLA mismatches. A 35–year–old man with idiopathic dilated cardiomyopathy with several previous hospitalizations for heart failure is admitted to our unit for a new episode in August 2021. After evaluation, the patient was placed on the waiting list for transplant. The following month the patient underwent heart transplant. The donor had a compatible CDC crossmatch and was negative for anti–HLA antibodies. After 46 days, the patient was discharged at home in stable conditions after 2 negative endomyocardial biopsies (EMB): ISHLT’04 0. In January 2021, the patient was newly admitted for dyspnea and oliguria. Imaging revealed bilateral severe pleural effusion, biventricular cardiac disfunction; EMB showed acute rejection (ISHLT’04 3R). Panel–reactive antibody (PRA) screening found 93 % of class I PRA, 3 % of class II PRA with IgM and IgG donor–specific antibodies (DSA), C1q–positive. After 2 months, the patient was placed again on the transplant waitlist for a persistent severe biventricular disfunction, massive tricuspid regurgitation and diffuse myocardial fibrosis; class I PRA was decreasing (41 % in March 2022, 31 % in April 2022). Unfortunately, the patient died of infection before re–transplantation. After the event, which was recognized as AMR caused by class I DSA, a form rarely described in literature, we employed the PIRCHE (Predicted Indirectly Recognizable HLA Epitopes) algorithm to predict indirect donor–recipient alloreactivity: PIRCHE–II was 54. Is a high PIRCHE–II score a reliable predictor of AMR following heart transplant? More data and deeper understanding is surely needed. A correct after–transplant serologic monitoring is definitely needed to search for de–novo DSA.

Molecular disparity of HLA-DPB1 is associated with the development of subsequent solid cancer after allogeneic hematopoietic stem cell transplantation.

An increased incidence of subsequent solid cancers (SSCs) has been reported in long-term survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT), and SSC is associated with inferior mortality and morbidity. Previous studies showed that the incidence of SSC is significantly higher in those who underwent allo-HSCT from HLA-mismatched donors, suggesting that persistent alloimmunity may predispose patients to SSCs. It was recently reported that, in a cohort of patients who received allo-HSCT from an unrelated donor matched at HLA-A, -B, -C, -DRB1/3/4/5, and -DQB1 loci, HLA-DPB1 alloimmunity determined by high mismatched eplets (MEs) and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE) score (PS), was associated with relapse protection and increased risk of acute graft-versus-host disease (GVHD). In the present study, the impact of HLA-DPB1 alloimmunity assessed by molecular mismatch algorithms on the development of SSCs in a cohort of 1514 patients who underwent allo-HSCT for hematologic malignancies was further investigated. ME load at the HLA-DPB1 locus was measured using the HLAMatchmaker module incorporated in HLA Fusion software, and the PS for mismatched HLA-DPB1 was calculated using the HSCT module from the PIRCHE online matching service. In multivariable analysis after adjusting for baseline risk factors, higher ME, PS-I, and PS-II in the GVH direction, but not in the HVG direction, were associated with an increased risk of SSCs (ME: subdistribution hazard ratio [SHR] 1.58, p= .01; PS-I: SHR 1.59, p= .009; PS-II: SHR 1.71, p= .003). In contrast, nonpermissive HLA-DPB1 mismatches defined by the conventional T-cell epitope algorithm were not predictive of the risk of SSCs. Moreover, posttransplant cyclophosphamide-based GVHD prophylaxis was associated with a reduced risk of subsequent solid cancer (SHR 0.34, p= .021). These results indicate for the first time that increased GVH alloreactivity could contribute to the development of SSCs in allo-HSCT survivors.

High PIRCHE Scores May Allow Risk Stratification of Borderline Rejection in Kidney Transplant Recipients.

BackgroundThe diagnosis of borderline rejection (BLR) ranges from mild inflammation to clinically significant TCMR and is associated with an increased risk of allograft dysfunction. Currently, there is no consensus regarding its treatment due in part to a lack of biomarkers to identify cases with increased risk for immune-mediated injury.MethodsWe identified 60 of 924 kidney transplant recipients (KTRs) with isolated and untreated BLR. We analyzed the impact of predicted indirectly recognizable HLA epitopes (PIRCHE) score on future rejection, de novo DSA development, and recovery to baseline allograft function. Additionally, we compared the outcomes of different Banff rejection phenotypes.ResultsTotal PIRCHE scores were significantly higher in KTRs with BLR compared to the entire study population (p=0.016). Among KTRs with BLR total PIRCHE scores were significantly higher in KTRs who developed TCMR/ABMR in follow-up biopsies (p=0.029). Notably, the most significant difference was found in PIRCHE scores for the HLA-A locus (p=0.010). PIRCHE scores were not associated with the development of de novo DSA or recovery to baseline allograft function among KTRs with BLR (p>0.05). However, KTRs under cyclosporine-based immunosuppression were more likely to develop de novo DSA (p=0.033) than those with tacrolimus, whereas KTRs undergoing retransplantation were less likely to recover to baseline allograft function (p=0.003).ConclusionsHigh PIRCHE scores put KTRs with BLR at an increased risk for future TCMR/ABMR and contribute to improved immunological risk stratification. The benefit of anti-rejection treatment, however, needs to be evaluated in future studies.

Analysis of biological models to predict clinical outcomes based on HLA-DPB1 disparities in unrelated transplantation

AbstractHLA compatibility is a key factor for survival after unrelated hematopoietic stem cell transplantation (HSCT). HLA-A, -B, -C, -DRB1, and -DQB1 are usually matched between donor and recipient. By contrast, HLA-DPB1 mismatches are frequent, although it is feasible to optimize donor selection and DPB1 matching with prospective typing. Because classical DPB1 allele mismatches are often unavoidable, however, several biological models have been developed to predict the optimal DPB1 mismatch combination for less graft-versus-host disease (GVHD) and better overall survival. In 909 recipient/donor pairs, we analyzed the role of 3 biological models: T-cell epitopes (TCEs) based on the immunogenicity of DPB1, cell surface expression of DPB1 molecules based on a single-nucleotide polymorphism located in the 3′ untranslated region, and the Predicted Indirectly ReCognizable HLA Epitopes (PIRCHE) model based on the presentation of allogeneic peptides derived from mismatched HLA, compared with the classical allele mismatch. Matching for both DPB1 alleles remains the best option to prevent acute GVHD. In the situation of one DPB1 allele mismatch, the donor associated with the lowest acute GVHD risks is mismatched for an allele with a low expression profile in the recipient, followed by a permissive TCE3/4 mismatch and/or the absence of PIRCHE II potential against the recipient. In the context of 2 DPB1 mismatches, the same considerations apply for a permissive TCE3/4 mismatch and no PIRCHE II. By combining the biological models, the most favorable DPB1 constellation can be defined. This approach will help optimize donor selection and improve post-HSCT complications and patient prognosis.

Intravenous immunoglobulins do not prove beneficial to reduce alloimmunity among kidney transplant recipients with BKV-associated nephropathy.

Reduced immunosuppression during BKV-DNAemia has been associated with T-cell mediated rejection (TCMR), de novo donor-specific antibodies (DSA) and antibody-mediated rejection (ABMR). Intravenous immunoglobulins (IVIG) may reduce alloimmunity. We studied 860 kidney transplant recipients (KTRs) for the development of BKV-DNAuria and BKV-DNAemia (low-level <10000IE/ml, high-level >10000IE/ml). 52/131 KTRs with high-level BKV-DNAemia received IVIG. The HLA-related immunological risk was stratified by the Predicted Indirectly Recognizable HLA Epitopes (PIRCHE) algorithm. BKV-DNAuria only was observed in 86 KTRs (10.0%), low-level BKV-DNAemia in 180 KTRs (20.9%) and high-level BKV-DNAemia in 131 KTRs (15.2%). KTRs with low-level BKV-DNAemia showed significantly less TCMR compared to KTRs with high-level BKV-DNAemia (5.2% vs. 25.5%; P<0.001) and no BKV-replication (13.2%; P=0.014), lowest rates of de novo DSA (21.3%), ABMR (9.2%) and flattest glomerular filtration rate (GFR) slope (-0.8ml/min). KTRs with low-level BKV-DNAemia showed significantly higher median (interquartile range) total PIRCHE if they developed TCMR [100.22 (72.6) vs. 69.52 (49.97); P=0.020] or ABMR [128.86 (52.99) vs. 69.52 (49.96); P=0.005]. Administration of IVIG did not shorten duration of BKV-DNAemia (P=0.798) or reduce TCMR, de novo DSA and ABMR (P>0.05). KTRs with low-level BKV-DNAemia showed best protection against alloimmunity, with a high number of PIRCHE co-determining the remaining risk. The administration of IVIG, however, was not beneficial in reducing alloimmunity.

Analysis of T and B Cell Epitopes to Predict the Risk of de novo Donor-Specific Antibody (DSA) Production After Kidney Transplantation: A Two-Center Retrospective Cohort Study.

Risk prediction of de novo donor specific antibody (DSA) would be very important for long term graft outcome after organ transplantation. The purpose of this study was to elucidate the association of eplet mismatches and predicted indirectly recognizable HLA epitopes (PIRCHE) scores with de novo DSA production. Our retrospective cohort study enrolled 691 living donor kidney transplantations. HLA-A, B, DRB and DQB eplet mismatches and PIRCHE scores (4 digit of HLA-A, B, DR, and DQ) were determined by HLA matchmaker (ver 2.1) and PIRCHE-II Matching Service, respectively. Weak correlation between eplet mismatches and PIRCHE scores was identified, although both measurements were associated with classical HLA mismatches. Class II (DRB+DQB) eplet mismatches were significantly correlated with the incidence of de novo class II (DR/DQ) DSA production [8/235 (3.4%) in eplet mismatch ≤ 13 vs. 92/456 (20.2%) in eplet mismatch ≥ 14, p < 0.001]. PIRCHE scores were also significantly correlated with de novo class II DSA production [26/318 (8.2%) in PIRCHE ≤ 175 vs. 74/373 (19.8%) in PIRCHE ≥ 176, p < 0.001]. Patients with low levels of both class II eplet mismatches and PIRCHE scores developed de novo class II DSA only in 4/179 (2.2%). Analysis of T cell and B cell epitopes can provide a beneficial information on the design of individualized immunosuppression regimens for prevention of de novo DSA production after kidney transplantation.

Exploring predicted indirectly recognizable HLA epitopes (PIRCHE-II) in liver transplant recipients on calcineurin inhibitor-free maintenance immunosuppression. A retrospective single center study

The PIRCHE (Predicted Indirectly ReCognizable HLA Epitopes) score is an HLA epitope matching algorithm. PIRCHE algorithm estimates the level of presence of T-cell epitopes in mismatched HLA. The PIRCHE-II numbers associate with de novo donor-specific antibody (dnDSA) formation following liver transplantation and kidney allograft survival following renal transplantation. The aim of our study was to assess the PIRCHE-II score in calcineurin inhibitor (CNI)-free maintenance immunosuppression recipients.This was a retrospective study of forty-one liver transplant recipients on CNI-free immunosuppression and with available liver allograft biopsies. Donors and recipients were HLA typed. The HLA-derived mismatched peptide epitopes that could be presented by the recipient's HLA-DRB1 molecules were calculated using PIRCHE-II algorithm. The associations between PIRCHE-II scores and graft immune-mediated events were assessed using receiver operating characteristics curves and subsequent univariate and multivariate analyses.CNI-free patients with cellular rejection, humoral rejection, or severe portal inflammation had higher mean PIRCHE-II scores compared to patients with normal liver allografts. PIRCHE-II score and donor age were independent risk factors for liver graft survival in CNI-free patients (HR: 8.0, 95% CI: 1.3–49, p = .02; and HR: 0.88, 95% CI: 0.00–0.96, p = .007, respectively).PIRCHE-II scores could be predictive of liver allograft survival in CNI-free patients following liver transplantation. Larger studies are needed to confirm these results.

Predicted Indirectly ReCognizable HLA Epitopes (PIRCHE) Are Associated with Poorer Outcome after Single Mismatch Unrelated Donor Stem Cell Transplantation: A Study of the Cooperative Transplant Study Group (KTS) of the German Group for Bone Marrow and Stem Cell Transplantation (DAG-KBT)

There is no established standard for selection of mismatched unrelated donors. Indirect recognition of HLA mismatches can be predicted using the model of “Predicted Indirectly ReCognizable HLA Epitopes” (PIRCHE). We performed a multicenter retrospective study evaluating the impact PIRCHE on outcome after allogeneic stem cell transplantation (allo-HSCT) from single mismatched (HLA 9/10 matched) unrelated donors. The study cohort included 424 adult recipients of HLA 9/10 matched unrelated donor transplants (9/10 MUD), treated for AML or MDS at 6 transplant centers across Germany. Detection of PIRCHE was associated with lower overall survival (OS) (47 vs. 57%, p = 0.04), higher non-relapse mortality (NRM) (32 vs. 20%, p = 0.05), and higher incidence of chronic graft-versus-host disease (GVHD) (49 vs. 31%, p = 0.04) at 2 years. Cumulative incidence of acute GVHD grade 2–4 at 6 months was not significantly different (30 vs. 23%, p = 0.2). OS for 9/10 MUD with no PIRCHE was similar to 10/10 MUD (57 vs. 55%). In multivariate analysis, PIRCHE retained negative impact on OS (RR 1.5, 95% CI 1.0–2.1, p = 0.03) and NRM (RR 1.7, 95% CI 1.0–2.9, p = 0.03). To the best of our knowledge, for the first time, we show the association of PIRCHE and survival outcome after allo-HSCT. The PIRCHE model, if validated in an independent cohort, may allow selection of permissible HLA mismatches that enable improved transplant outcome.

Exploratory Study of Predicted Indirectly ReCognizable HLA Epitopes in Mismatched Hematopoietic Cell Transplantations.

HLA-mismatches in hematopoietic stem-cell transplantation are associated with an impaired overall survival (OS). The aim of this study is to explore whether the Predicted Indirectly ReCognizable HLA-Epitopes (PIRCHE) algorithm can be used to identify HLA-mismatches that are related to an impaired transplant outcome. PIRCHE are computationally predicted peptides derived from the patient's mismatched-HLA molecules that can be presented by donor-patient shared HLA. We retrospectively scored PIRCHE numbers either presented on HLA class-I (PIRCHE-I) or class-II (PIRCHE-II) for a Dutch multicenter cohort of 103 patients who received a single HLA-mismatched (9/10) unrelated donor transplant in an early phase of their disease. These patients were divided into low and high PIRCHE-I and PIRCHE-II groups, based on their PIRCHE scores, and compared using multivariate statistical analysis methods. The high PIRCHE-II group had a significantly impaired OS compared to the low PIRCHE-II group and the 10/10 reference group (HR: 1.86, 95%-CI: 1.02–3.40; and HR: 2.65, 95%-CI: 1.53–4.60, respectively). Overall, PIRCHE-II seem to have a more prominent effect on OS than PIRCHE-I. This impaired OS is probably due to an increased risk for severe acute graft-vs.-host disease. These data suggest that high PIRCHE-II scores may be used to identify non-permissible HLA mismatches within single HLA-mismatched hematopoietic stem-cell transplantations.

Class I Graft-Versus-Host Mismatch Based on Predicted Indirectly Recognizable HLA Epitopes (PIRCHES) Is Associated with Worse Post-Transplant Outcomes in Patients Receiving Peripheral Blood, T-Cell Replete Haploidentical Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide

Introduction High dose post-transplant cyclophosphamide has improved the outcomes and expanded the use of haploidentical hematopoietic cell transplantation (haplo-HCT). The impact of HLA disparity in this setting, however, is unclear and is traditionally measured at the antigen or allele level. The Predicted Indirectly Recognizable HLA Epitopes (PIRCHES) model provides a novel tool to calculate the number of mismatched HLA peptides between donor and host that can be processed and presented by shared HLA antigens for T cell recognition. No data exist on the relationship between PIRCHES mismatch and clinical outcome in haplo-HCT with post-transplant cyclophosphamide. Methods 148 patients who received a peripheral blood, T-cell replete haplo-HCT with post-transplant cyclophosphamide at a single center between 2009 and 2016 were retrospectively analyzed. The PIRCHES mismatch load was calculated using the PIRCHES matching tool online and was categorized by class and vector. The primary outcome was incidence of relapse. The association between PIRCHES mismatch and outcome was analyzed using the Cox proportional hazard model or Gray's sub-distribution method for competing risk as appropriate. This study was approved by the Institutional Review Board. Results The median follow-up for survivors was 34.0 months (range, 14.5-78.3 months). One-hundred (67.6%) patients were deceased and 61 (41.2%) patients relapsed during follow-up. Class I graft-versus-host (GvH) PIRCHES mismatch had a median of 11 with a range of 0 to 56. Class II GvH PIRCHES mismatch had a median of 29 with a range of 0 to 122. Class I GvH PIRCHES mismatch was associated with worse acute graft-versus-host disease (aGvHD) (grades II-IV) (HR 1.021 per unit PIRCHES mismatch increase; 95% CI 1.001-1.040; p=0.036). Class I GvH PIRCHES mismatch was not associated with treatment-related mortality (TRM), but was associated with a trend towards worsened overall survival (OS) (HR 1.015 per unit PIRCHES mismatch increase; 95% CI 0.999-1.033; p=0.073). Class I host-versus-graft (HvG) PIRCHES mismatch was associated with worse relapse-free survival (RFS) (HR 1.018; 95% CI 1.001-1.035; p=0.036) and worse OS (HR 1.018; 95% CI 1.001-1.035; p=0.036) but not relapse. Class II PIRCHES mismatch was not associated with relapse, OS, RFS, TRM, or aGvHD. Both class I and II PIRCHES mismatch were not associated with chronic GvHD or engraftment. Discussion Class I GvH PIRCHES mismatch was associated with greater aGvHD and a trend towards worsened OS, while class I HvG PIRCHES mismatch was associated with worsened RFS and OS. Class II PIRCHES mismatch was not associated with outcomes and appears to be tolerated by this patient cohort. PIRCHES mismatch represents a novel strategy to predict clinical outcome in haplo-HCT. Further studies using registry data and prospective studies are needed to validate these findings.

Donor-Recipient Matching Based on Predicted Indirectly Recognizable HLA Epitopes Independently Predicts the Incidence of De Novo Donor-Specific HLA Antibodies Following Renal Transplantation.

De novo donor-specific HLA antibodies (dnDSA) are recognized as a risk factor for premature allograft failure. Determinants of DSA specificity are generated via the indirect allorecognition pathway. Here, we present supportive data for the relevance of predicted indirectly recognizable HLA epitopes (PIRCHE) to predict dnDSA following kidney transplantation. A total of 2787 consecutive kidney transplants performed between 1995 and 2015 without preformed DSA have been analyzed. De novo DSA were detected by single antigen bead assay. HLA epitope mismatches were determined by the HLAMatchmaker and PIRCHE approach and correlated in uni- and multivariate analyses with 10-year allograft survival and incidence of dnDSA. The PIRCHE-II score moderately predicted allograft survival. However, the predictive value of elevated PIRCHE-II scores >9 for the incidence of dnDSA was statistically significant (p < 0.001). In a multivariate Cox regression analysis adjusted for antigen mismatch and HLAMatchmaker epitopes, the PIRCHE-II score could be identified as an independent risk factor for dnDSA. The PIRCHE-II score independently from the antigen mismatch and HLAMatchmaker epitopes could be revealed as being a strong predictor for dnDSA. PIRCHE may help to identify acceptable mismatches with decreased risk of dnDSA and thus improve long-term renal allograft survival.

200 - Analysis of Predicted Indirectly Recognizable HLA Epitopes (PIRCHE) in Mismatched Unrelated Donor Hematopoietic Stem Cell Transplants (HCT): A Center for International Blood and Marrow Transplant Research (CIBMTR) Cohort Study

200 - Analysis of Predicted Indirectly Recognizable HLA Epitopes (PIRCHE) in Mismatched Unrelated Donor Hematopoietic Stem Cell Transplants (HCT): A Center for International Blood and Marrow Transplant Research (CIBMTR) Cohort Study

Predicted Indirectly ReCognizable HLA Epitopes Class I Promote Antileukemia Responses after Cord Blood Transplantation: Indications for a Potential Novel Donor Selection Tool.

Unrelated cord blood transplantation (UCBT) provides a curative therapy for patients with hematological malignancies. The effect of HLA mismatches in UCBT is currently the subject of debate. HLA-mismatched UCBT may lead to improved leukemia control but also to graft-versus-host disease (GVHD), resulting in nonrelapse mortality (NRM). The aim of this study was to investigate whether indirect recognition of mismatched HLA provides an explanation for the graft-versus-tumor effect and risk of GVHD. The probability of indirect recognition was predicted by the Predicted Indirectly ReCognizable HLA Epitopes (PIRCHE) model. The effect of the numbers of PIRCHE presented on HLA class I and II (PIRCHE-I and -II) was studied in 134 pediatric patients. To study the effects of higher numbers of PIRCHE, patients were divided in 2 equally sized groups, using the median number of PIRCHE as cutoff values. Proportional hazard models and competing risk analyses were performed to study the effect of PIRCHE on the clinical outcomes relapse, acute and chronic GVHD, NRM, and disease-free and overall survival. Above median PIRCHE-I were associated with reduced relapse risk (HR, .26; 95% CI, .07 to .94; P= .04), evaluating the 50 patients transplanted for a malignancy. Both PIRCHE-I and -II were not associated with other clinical outcomes, including GVHD and NRM. These data suggest that high PIRCHE-I may lead to improved graft-versus-tumor effects after UCBT, without an accompanying GVHD risk. Inclusion of PIRCHE in UCB selection criteria may enhance UCBT outcome, which needs to be tested in prospective studies.

The number of T cell allo-epitopes associates with CD4+ and CD8+ T-cell infiltration in pediatric cutaneous GVHD

Risk factors for graft-versus-host disease (GVHD) following allogeneic hematopoietic stem-cell transplantation (HCST) include: HLA mismatches, sex-mismatch, and stem-cell source. We retrospectively analyzed if HLA- and sex-mismatching quantitatively affects the composition of GVHD-induced T-cell infiltrates. We quantified absolute numbers of CD4+ and CD8+ T cells present in tissue sections from skin biopsies of 23 pediatric HSCT-recipients with GVHD. HSCT with a sex-mismatched unrelated donor was associated with an increased number of CD4+ T cells when compared to a sex-matched unrelated donor (p=0.01). The absolute numbers of skin-infiltrating T cells were increased in patients expressing T-cell epitopes derived from the recipient’s mismatched HLA, so called predicted indirectly recognizable HLA epitopes (PIRCHE). The combined expression of PIRCHE with a sex-mismatch resulted in the highest number of skin-infiltrating T cells. Our results indicate that an increased number of recipient-specific T-cell epitopes is associated with accumulation of CD4+ and CD8+ T cells in the skin.

Complete donor chimerism is a prerequisite for the effect of Predicted Indirectly ReCognizable HLA Epitopes (PIRCHE) on acute graft-versus-host disease.

Predicted indirectly recognizable HLA epitopes (PIRCHE) computationally predict donor T-cell recognition of mismatched-HLA derived peptides following allogeneic haematopoietic stem-cell transplantation (allo-HSCT), as is evidenced by the correlation between presence of HLA-DPB1-derived PIRCHE and the occurrence of graft-vs.-host disease (GVHD). Complete donor T-cell chimerism associates with an increased GVHD risk compared to mixed patient and donor chimerism. If the correlation between the presence of PIRCHE and GVHD occurrence is indeed mediated by donor T cells, the presence of donor T cells should be required to observe such a correlation. This study was initiated to investigate whether the effect of PIRCHE is different in patients with complete chimerism compared to those with mixed chimerism. Indeed, the correlation between PIRCHE and GVHD is present in patients with complete chimerism, whereas it is absent in those with mixed chimerism. The data presented here suggest that chimerism status is important for the detection of potential GVHD epitopes.

Refinement of the Definition of Permissible HLA-DPB1 Mismatches with Predicted Indirectly ReCognizable HLA-DPB1 Epitopes

Hematopoietic stem cell transplantation with HLA-DPB1–mismatched donors leads to an increased risk of acute graft-versus-host disease (GVHD). Studies have indicated a prognostic value for classifying HLA-DPB1 mismatches based on T cell–epitope (TCE) groups. The aim of this study was to determine the contribution of indirect recognition of HLA-DP–derived epitopes, as determined with the Predicted Indirectly ReCognizable HLA Epitopes (PIRCHE) method. We therefore conducted a retrospective single-center analysis on 80 patients transplanted with a 10/10 matched unrelated donor that was HLA-DPB1 mismatched. HLA-DPB1 mismatches that were classified as GVH nonpermissive by the TCE algorithm correlated to higher numbers of HLA class I as well as HLA class II presented PIRCHE (PIRCHE-I and -II) compared with permissive or host-versus-graft nonpermissive mismatches. Patients with acute GVHD grades II to IV presented significantly higher numbers of PIRCHE-I compared with patients without acute GVHD (P < .05). Patients were divided into 2 groups based on the presence or absence of PIRCHE. Patients with PIRCHE-I or -II have an increased hazard of acute GVHD when compared with patients without PIRCHE-I or -II (hazard ratio [HR], 3.19; 95% confidence interval [CI], 1.10 to 9.19; P < .05; and HR, 4.07; 95% CI, .97 to 17.19; P = .06, respectively). Patients classified as having an HLA-DPB1 permissive mismatch by the TCE model had an increased risk of acute GVHD when comparing presence of PIRCHE-I with absence of PIRCHE-I (HR, 2.96; 95% CI, .84 to 10.39; P = .09). We therefore conclude that the data presented in this study describe an attractive and feasible possibility to better select permissible HLA-DPB1 mismatches by including both a direct and an indirect recognition model.

Indirectly Recognized HLA-C Mismatches and Their Potential Role in Transplant Outcome

HLA-C mismatches are clearly associated to alloreactivity after hematopoietic stem-cell transplantation; in a number of large cohorts, HLA-C mismatches are correlated to an increased risk of acute graft-versus-host disease (GVHD) or even impaired survival. While for HLA-A and -B, both antigenic as well as allelic mismatches are associated with an increased risk of acute GVHD, such an increased risk is only observed for antigenic HLA-C mismatches and not for allelic mismatches. These observations raise the question what sets HLA-C apart from HLA-A and -B. The difference may well be related to the reduced levels of cell-surface expression of HLA-C as compared to HLA-A and -B, possibly due to, among other factors, a limited peptide-binding capacity. This limited peptide-binding capacity may retain HLA-C in the ER and enhance degradation of the HLA-C protein. Once degraded, HLA-C-derived peptides can be presented to the immune system via other HLA alleles and are thus available for indirect recognition. Indeed, such HLA-C-derived peptides have previously been eluted from other HLA alleles. We have recently developed an approach to predict indirect recognition of HLA molecules, by establishing the numbers of predicted indirectly recognizable HLA epitopes (PIRCHES). The number of PIRCHES presented on HLA class I and II (PIRCHE-I and -II, respectively), are highly correlated to clinical measures of alloreactivity, such as acute GVHD. In the present “Hypothesis & Theory,” we reviewed the current knowledge on HLA-C mismatches and alloreactivity. Moreover, we speculate about the role of direct and indirect recognition of HLA-C and the consequences for donor selection in HLA-C mismatched stem-cell transplantation.