The Degree of Phylogenetic Disparity of Islet Grafts Dictates the Reliance on Indirect CD4 T-Cell Antigen Recognition for Rejection

  1. Gina R. Rayat1,
  2. Zachary A. Johnson1,
  3. Joshua N. Beilke1,
  4. Gregory S. Korbutt2,
  5. Ray V. Rajotte2 and
  6. Ronald G. Gill1
  1. 1Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Denver, Colorado
  2. 2Surgical-Medical Research Institute, University of Alberta, Edmonton, Alberta, Canada

    Abstract

    Cellular xenograft rejection involves a pronounced contribution of CD4 T-cells recognizing antigens in association with recipient MHC class II molecules. However, the requirement for such “indirect” antigen recognition for acute islet xenograft is not clear, especially as a function of the phylogenetic disparity between the donor and recipient species. In vitro studies show that C57BL/6 (B6) mouse T-cells respond directly to either allogeneic BALB/c or phylogenetically related xenogeneic WF rat stimulator cells while having undetectable responses to phylogenetically disparate porcine stimulator cells. Although all types of grafts rejected acutely in wild-type mice, this response demonstrated markedly differing dependence on host MHC class II antigen presentation, depending on the donor species. While BALB/c islet allografts were acutely rejected in B6 MHC class II-deficient (C2D) recipients, WF rat xenografts demonstrated marked prolongation in C2D hosts relative to wild-type recipients. Interestingly, neonatal porcine islet (NPI) xenografts uniformly survived long term (>100 days) in untreated C2D hosts despite transfer of wild-type CD4 T-cells, demonstrating that survival in C2D recipients was not secondary to a lack of CD4 T-cells seen in such mice. Taken together, these results show a marked hierarchy in the requirement for host MHC class II-restricted indirect pathway in the rejection of pancreatic islet grafts. Thus, while cellular rejection of porcine xenografts is generally quite vigorous, this pathway is relatively finite, displaying a major reliance on host MHC class II-dependent antigen presentation for acute rejection.

    Footnotes

    • Address correspondence and reprint requests to Dr. Ronald G. Gill, Barbara Davis Center for Childhood Diabetes, Box-B140, University of Colorado Health Sciences Center, 4200 East 9th Ave., Denver, CO 80262. E-mail: ron.g.gill{at}uchsc.edu.

      Received for publication 23 July 2002 and accepted in revised form 6 March 2003.

      ABC/HP, avidin-biotin complex/horseradish peroxidase; APC, antigen-presenting cell; BD, Becton Dickinson; C2D, MHC class II-deficient; CTL, cytotoxic T-lymphocyte; MLR, mixed lymphocyte reaction; NPI, neonatal porcine islet.

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