The strength of cell-mediated xenograft rejection in the mouse is due to the CD4+ indirect response

Xenotransplantation. 1998 Feb;5(1):93-8. doi: 10.1111/j.1399-3089.1998.tb00014.x.


Previous studies have shown that CD4+ T cells are responsible for the great strength of cell-mediated xenograft rejection in the mouse. In vitro studies have suggested that this CD4+ response is to xenogeneic antigens that are presented indirectly. The present studies were carried out in order to determine whether the strength of cell-mediated xenograft rejection in vivo is dependent on the CD4+ indirect response. We grafted pig skin onto mice that express class II MHC antigens only on their thymic epithelial cells (II-4+ mice). These mice have normal numbers of functional peripheral CD4+ T cells; however they lack class II MHC expression on their antigen presenting cells and are thus incapable of mounting a CD4+ T cell-mediated indirect response. Xenograft survival was prolonged on these mice. Furthermore, administration of cyclosporine and anti-CD8 monoclonal antibodies to II-4+ recipients prolonged xenograft survival to at least the same extent as allograft survival, demonstrating that the strength of cell-mediated xenograft rejection resides in the CD4+ indirect response. Despite the increased survival time, xenograft rejection still occurred in the absence of the indirect pathway. Depletion of the II-4+ recipients of their CD4+ T cell population prolonged xenograft survival even further, suggesting the presence of a weaker CD4+ direct mechanism which was virtually undetectable in vitro.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology*
  • Cyclosporine / pharmacology
  • Cytokines / biosynthesis
  • Graft Rejection / etiology*
  • Graft Rejection / immunology*
  • Graft Survival / immunology
  • Histocompatibility Antigens Class II / genetics
  • Histocompatibility Antigens Class II / metabolism
  • Immunity, Cellular
  • Immunosuppressive Agents / pharmacology
  • In Vitro Techniques
  • Mice
  • Mice, Inbred A
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Skin Transplantation / adverse effects
  • Skin Transplantation / immunology
  • Swine
  • Swine, Miniature
  • Transplantation, Heterologous / adverse effects*
  • Transplantation, Heterologous / immunology*


  • Cytokines
  • Histocompatibility Antigens Class II
  • Immunosuppressive Agents
  • Cyclosporine