Induction of Alloanergy in Human Donor T Cells Without Loss of Pathogen or Tumor Immunity

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Abstract
Human leukocyte antigen (HLA)-mismatched allogeneic hematopoietic stem cell transplantation (HSCT) is limited by acute graft-versus-host disease (aGvHD). Nonselective T-cell depletion effectively prevents severe aGvHD but profoundly impairs donor-derived immune reconstitution, increasing infection and disease relapse. The strategy of induction of alloantigen-specific hyporesponsiveness (“alloanergization”) in donor bone marrow by allostimulation with costimulatory blockade before haploidentical transplantation has demonstrated early promise in reducing severe aGvHD. However, the differential effect of alloanergization on CD4+ and CD8+ donor T-cell subsets and the degree to which beneficial pathogen- and tumor-immune responses are retained have not been extensively examined. We used an in vitro model of alloanergization by allostimulation of human donor T cells with irradiated unrelated recipient peripheral blood mononuclear cells and costimulatory blockade with humanized monoclonal anti-B7.1 and B7.2 antibodies. Residual alloresponses were assessed by proliferation (thymidine uptake, carboxyfluorescein diacetate succinimidyl ester dye dilution) and cytotoxicity assays. Retention of human herpes virus and tumor-associated antigen (TAA)-specific immunity was measured with HLA-class I-restricted pentamers, intracellular cytokine secretion, and CD107a assay using 5-color flow cytometry. Alloanergization of HLA-mismatched donor T cells efficiently and selectively abrogated recipient-specific alloproliferation in both CD4+ and CD8+ cells while preserving functional CD4+ and CD8+ immune responses to clinically important human herpes viruses and to the TAA WT1. Retention of pathogen- and TAA-specific immunity after alloanergization demonstrates that this methodology, which is simple to apply, has potential to improve immune reconstitution while limiting alloreactivity after HLA-mismatched hematopoietic stem cell transplantation, and deserves additional evaluation in further human clinical trials.