HLA class II upregulation during viral infection leads to HLA-DP–directed graft-versus-host disease after CD4+ donor lymphocyte infusion

Abstract

Key Points• GVHD after HLA-DPB1-mismatched CD41 DLI after TCD-alloSCT is mediated by allo-reactive HLA-DPB1-directed CD41 T cells.• Viral infections after TCDalloSCT can induce HLA class II on nonhematopoietic tissues, making them targets for CD41 T cells in GVHD.CD81 T cell-depleted (TCD) donor lymphocyte infusion (DLI) after TCD allogeneic hematopoietic stem cell transplantation (alloSCT) has been associated with a reduced risk of graft-versus-host disease (GVHD) while preserving conversion to donor hematopoiesis and antitumor immunity, providing a rationale for exploring CD41 T cell-based immunotherapy for hematologic malignancies. Here, we analyzed the clinical course and specificity of T cell immune responses in 2 patients with acute myeloid leukemia (AML) who converted to full-donor chimerism but developed severe acute GVHD after prophylactic CD41 DLI after 10/10-HLA-matched, but HLA-DPB1-mismatched TCD-alloSCT. Clonal analysis of activated T cells isolated during GVHD demonstrated allo-reactivity exerted by CD41 T cells directed against patient-mismatched HLA-DPB1 molecules on hematopoietic cells and skin-derived fibroblasts only when cultured under inflammatory conditions. At the time of CD41 DLI, both patients contained residual patient-derived T cells, including cytomegalovirus (CMV)-specific T cells as a result of CMV reactivations.Once activated by CMV antigens, these CMV-specific T cells could stimulate HLA-DPB1-specific CD41 T cells, which in turn could target nonhematopoietic tissues in GVHD. In conclusion, our data demonstrate that GVHD after HLA-DPB1-mismatched CD41 DLI can be mediated by allo-reactive HLA-DPB1-directed CD41 T cells and that ongoing viral infections inducing HLA class II expression on nonhematopoietic cells may increase the likelihood of GVHD development. This trial is registered at http://www.controlled-trials.com/ISRCTN51398568/LUMC as #51398568. (Blood. 2013;122(11):1963-1973 IntroductionIn allogeneic hematopoietic stem cell transplantation (alloSCT), T-cell depletion of the graft efficiently prevents the occurrence of severe acute graft-versus-host disease [GVHD]) 1,2 but also adversely affects posttransplant antitumor and antipathogen immunity.1-3 Early intervention with donor lymphocyte infusion (DLI) after T cell-depleted (TCD)-alloSCT may prevent relapse of the malignancy and improve immune reconstitution against pathogens but is frequently associated with reintroduction of GVHD. 4,5 Therefore, exploration of treatment strategies to improve the balance between graft-versus-leukemia (GVL) reactivity and antipathogen immunity and GVHD is warranted.To minimize the risk of GVHD, patients are preferably transplanted with stem cell grafts from HLA-matched sibling or unrelated donors (URD).6 HLA matching is generally performed for HLA-A, -B, -C, -DRB1, and -DQB1 alleles (10/10 match) but not for HLA-DPB1. Therefore, 70% to 80% of URD alloSCT are HLA-DPB1-mismatched. 6,7 In contrast to HLA class I, constitutive expression of HLA class II molecules is mainly confined to normal...

Allogeneic HY antibodies detected 3 months after female-to-male HCT predict chronic GVHD and nonrelapse mortality in humans

“…Viral infections can induce HLA class II on nonhematopoietic tissues, making them targets for alloreactive CD4 1 T cells that may elicit aGVHD. 25 Similarly, CMV inflammation via alloreactive CD4 1 T cells may augment H-Y humoral immunity indirectly, although the mediators remain to be determined.…”

New strategies of DLI in the management of relapse of hematological malignancies after allogeneic hematopoietic SCT

“…54 Currently, preemptive and prophylactic DLI (pDLI) is widely used to minimize the risk of post-transplant relapse for patients receiving T-cell depletion 55 and having diseases at advanced stage. 55,56 pDLI is also often administered for promoting FDC, enhancing immune reconstitution, 27,57,58 as well as treating virus infection after HSCT and preventing viral reactivation.…”

“…HLA-DPB1 is often not taken into consideration in donor selection because it has no significant effect on overall mortality of patients in allotransplant; 54 however, HLA-DPB1-mismatched allo-HSCT is associated with a decreased risk of disease relapse and an increased risk of GVHD compared with HLA-DPB1-matched allo-HSCT. [91][92][93][94] As described in some studies, 19,92 in T-cell-depleted allo-HSCT, mismatching for HLA-DPB1 was not associated with an increased risk of GVHD, but highly correlated with a significantly decreased risk of disease relapse.…”

HLA-DP in unrelated hematopoietic cell transplantation revisited: challenges and opportunities

“…33 Moreover, alloreactive T cells targeted to LEL have been recovered from patients with GVHD and GVL. [34][35][36][37] Due to strong linkage disequilibrium (LD) between HLA-DRB1 and -DRB3/4/5 and -DQ, mismatches for these LEL are relatively rare in UD-HCT. In contrast, HLA-DP mismatches are present in over 80% of HLA-matched UD-HCT, reflecting their low LD with the other class II loci.…”