Alloimmunogenicity of an isolated MHC allele is affected by the context of MHC mismatch in a murine model.

Abstract

Humoral alloimmunization to human leukocyte antigen (HLA) can represent a barrier to solid-organ transplantation, can lead to a refractory state in patients requiring platelet transfusion, and can also contribute to transfusion-related acute lung injury (TRALI). While exposure to HLA-mismatched cells/tissues are generally required for HLA alloimmunization, the effect of the extent of major histocompatibility complex (MHC) mismatch between donor and recipient is poorly understood. A novel mouse was generated that allows the expression of a single MHC Class I alloantigen, Kd . Alloimmune responses to Kd were studied in C57BL/6 mice transfused with splenocytes from different donor mice, allowing the analysis of responses to Kd as an isolated alloantigen, or in the context of additional mismatched MHC molecules. Advanced tools were utilized to study responses to Kd , including T-cell receptor transgenic mice that recognize the immunodominant Kd peptide presented by C57BL/6 mice to CD4+ T cells. A single MHC Class I alloantigen mismatch is less immunogenic than when the same alloantigen is encountered in the context of additional mismatched MHC alloantigens. This difference is due, at least in part, to induction of CD4+ helper T cells, as the effect is overcome by increasing either mature CD4+ T-cell help through immunization or by increasing the precursor frequency of naïve CD4+ T cells by adoptive transfer from T-cell receptor transgenic donors. These findings indicate that the immunogenicity of a single alloantigen can be affected by the context in which it is encountered, demonstrating the potential for cooperative effects between different mismatched MHC alloantigens.