CD4 Donor Lymphocyte Infusion Can Cause Conversion of Chimerism Without GVHD by Inducing Immune Responses Targeting Minor Histocompatibility Antigens in HLA Class II

Abstract

Under non-inflammatory conditions HLA class II is predominantly expressed on hematopoietic cells. Therefore, donor CD4 T-cells after allogeneic stem cell transplantation (alloSCT) may mediate graft-vs.-leukemia reactivity without graft-vs.-host disease (GVHD). We analyzed immune responses in four patients converting from mixed to full donor chimerism without developing GVHD upon purified CD4 donor lymphocyte infusion (DLI) from their HLA-identical sibling donor after T-cell depleted alloSCT. In vivo activated T-cells were clonally isolated after CD4 DLI. Of the alloreactive T-cell clones, 96% were CD4 positive, illustrating the dominant role of CD4 T-cells in the immune responses. We identified 9 minor histocompatibility antigens (MiHA) as targets for alloreactivity, of which 8 were novel HLA class II restricted MiHA. In all patients, MiHA specific CD4 T-cells were found that were capable to lyse hematopoietic cells and to recognize normal and malignant cells. No GVHD was induced in these patients. Skin fibroblasts forced to express HLA class II, were recognized by only two MiHA specific CD4 T-cell clones. Of the 7 clones that failed to recognize fibroblasts, two targeted MiHA were encoded by genes not expressed in fibroblasts, presentation of one MiHA was dependent on HLA-DO, which is absent in fibroblasts, and T-cells recognizing the remaining 4 MiHA had an avidity that was apparently too low to recognize fibroblasts, despite clear recognition of hematopoietic cells. In conclusion, purified CD4 DLI from HLA-identical sibling donors can induce conversion from mixed to full donor chimerism with graft-vs.-malignancy reactivity, but without GVHD, by targeting HLA class II restricted MiHA.

Minor Histocompatibility Antigen-Specific T Cells

“…As such, class II-restricted minor H antigens may be more likely to induce a selective GVL response even if the gene encoding the minor H antigen is relatively broadly expressed. In a recent study of CD4 + enriched DLI from HLA-identical sibling donors, GVL reactivity without GVHD was associated with CD4 + T cells targeting HLA class II-restricted minor H antigens, some of which were associated with genes expressed in non-hematopoietic cells (97). However, HLA class II gene expression is often downregulated on leukemic cells after HCT (98,99), which implies that while class IIrestricted minor H antigen-specific T cells may make a major contribution to GVL after HCT and drive the HLA class II downregulation, class II-restricted minor H antigens may not be optimal targets for T cell immunotherapy to treat post-HCT relapse.…”

HA-1H T-Cell Receptor Gene Transfer to Redirect Virus-Specific T Cells for Treatment of Hematological Malignancies After Allogeneic Stem Cell Transplantation: A Phase 1 Clinical Study

“…Although chemotherapy and/or irradiation is part of the essential conditioning treatment to allow engraftment of donor hematopoietic cells, the advantage of alloSCT over high dose chemotherapy or autologous stem cell transplantation is the potential profound effect of the alloimmune response mediated by donor T cells resulting in eradication or persistent control of the malignant hematopoietic clone in the patient (1). After HLA-matched alloSCT, this graft vs. leukemia (GVL) reactivity is mainly mediated by donor T cells recognizing minor histocompatibility antigens (MiHA) on recipient hematopoietic cells (2)(3)(4)(5)(6). If donor T cells recognize MiHA expressed on both recipient hematopoietic and non-hematopoietic cells, GVL reactivity is frequently accompanied by graft-vs.-host disease (GVHD) (7)(8)(9)(10).…”

Discovery and Differential Processing of HLA Class II-Restricted Minor Histocompatibility Antigen LB-PIP4K2A-1S and Its Allelic Variant by Asparagine Endopeptidase

“…These T-cells are directed against minor histocompatibility antigens, which are polymorphic peptides differentially presented on patient and donor cells that are able to elicit CD8 + or CD4 + donor T-cells in the context of self-HLA (3). A variety of HLA-class I-and IIrestricted minor histocompatibility antigens have been identified by different techniques (4)(5)(6)(7)(8)(9)(10)(11), and for several of these antigens, the appearance of specific CD8 + T-cells was closely followed by complete remissions of the malignancies (12)(13)(14)(15), indicating the clinical relevance of these T-cells.…”