The Degree of Phylogenetic Disparity of Islet Grafts Dictates the Reliance on Indirect CD4 T-Cell Antigen Recognition for Rejection
- Gina R. Rayat1,
- Zachary A. Johnson1,
- Joshua N. Beilke1,
- Gregory S. Korbutt2,
- Ray V. Rajotte2 and
- Ronald G. Gill1
- 1Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Denver, Colorado
- 2Surgical-Medical Research Institute, University of Alberta, Edmonton, Alberta, Canada
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.
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:.
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.