Introduction

We have recently demonstrated that indirect-pathway responses against different alloantigens differ in their strength and longevity; specifically, that indirect responses against MHC class I alloantigen are long-lived, whilst those against class II alloantigen are, in similar fashion to direct-pathway responses, short-lived due to rapid clearance of donor APCs. Here we demonstrate how this knowledge may be used to inform immunoregulatory therapy with antigen-specific regulatory T cells (Tregs).

Methods

An MHC-mismatched murine model of cardiac transplantation was used [bm12.Kd.IE to C57BL6]. Polyclonal and antigen specific Tregs were generated by culture of CD4 T cells, utilising either syngeneic C57BL/6 or T cell receptor transgenic CD4 T cells specific for self-restricted donor class I (TCR75) and class II (TEa) allopeptide. To limit donor class I expression to haematopoietic cells, bone marrow chimeric donors were incorporated (bm12.Kd.IE bone marrow to lethally irradiated bm12.IE). T-regs were administered either at the time of, or 3 weeks after, transplantation, and their impact on the development of alloantibody and allograft vasculopathy evaluated.

Results

When given on the day of transplant, although polyclonal Tregs attenuated germinal centre allo and autoantibody responses and reduced allograft vasculopathy, monoclonal populations of class I and II allopeptide-specific indirect pathway Tregs were more effective. Moreover, when transferred late (3 weeks) after transplantation, only class I indirect Tregs proved effective at ameliorating chronic rejection, presumably because presentation of alloantigen is limited at this stage to self-restricted MHC class I alloantigen. In support, class I specific Tregs were ineffective at preventing progression of allograft vasculopathy when administered late to recipients of heart allografts from bone marrow chimeric donors, in which indirect-pathway responses against MHC class I alloantigen were truncated due to restricted expression of the alloantigen on short-lived haematopoietic cells.

Conclusion

Antigen specific Treg are more effective than polyclonal Treg at abrogating alloimmune responses and allograft vasculopathy. Their effectiveness when administered at late time points after transplantation is, nevertheless, dependent upon ongoing presentation of target allopeptide.

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