title: The degree of phylogenetic disparity of islet grafts dictates the reliance on indirect CD4 T-cell antigen recognition for rejection.
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.
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, 4200 East 9th Avenue, Denver, CO 80262, USA.
authors.forename: Gina R
authors.initials: GR
authors.lastname: Rayat
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Johnson
authors.forename: Joshua N
authors.initials: JN
authors.lastname: Beilke
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Korbutt
authors.forename: Ray V
authors.initials: RV
authors.lastname: Rajotte
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Gill
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003921:Diabetes Mellitus, Experimental / Q000601:surgery; D005260:Female; D014644:Genetic Variation; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D017710:Lymphocyte Transfusion; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010802:Phylogeny; D051381:Rats; D011920:Rats, Inbred WF; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014183:Transplantation, Heterologous / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D015704:CD4 Antigens; D000949:Histocompatibility Antigens Class II