CTLA-4lg in combination with anti-CD40L prolongs xenograft survival and inhibits anti-Gal Ab production in GT-Ko mice

Dengping Yin, Lianli Ma, Jikun Shen, Guerard W. Byrne, John S. Logan, Anita S.F. Chong

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

The generation of GT-Ko mice has provided unique opportunities to study allograft and xenograft rejection in the context of anti-α1,3-Gal antibody (anti-Gal Ab) responses. In this study we used the allotrans-plantation model of C3H hearts into galactosyl-transferase-deficient (GT-Ko) mice and the xenotrans-plantation model of baby Lewis rat hearts into GT-Ko mice to investigate the ability of CTLA-4lg in combination with anti-CD40L mAb to control graft rejection and anti-Gal Ab production. Murine CTLA-4lg or anti-CD40L monotherapy prolonged allograft survival, and the combination of these reagents was most immuno-suppressive. However short-term treatment with murine cytotoxic T lymphocyte associated antigen-4 (muCTLA-4lg) and/or CD40 ligand (CD154) monoclonal antibodies (anti-CD40L mAbs) was unable to induce indefinite allograft survival. CTLA-4-immunoglobulin fusion protein (CTLA-4lg) or anti-CD40L monotherapy only marginally prolonged xenograft survival; the combination of human CTLA-4lg and anti-CD40L significantly prolonged xenograft survival (74days), while the combination of murine CTLA-4lg and anti-CD40L resulted in graft survival of >120days. CTLA-4lg or anti-CD40L monotherapy or the combination of these agents inhibited the production of alloAbs, including anti-Gal Abs. CTLA-4lg or anti-CD40L monotherapy partially controlled xenoAb and anti-Gal Ab production, while the combination was more effective. These observations corroborate our previous observations that humoral, including anti-Gal Ab, responses and rejection following allograft or concordant xenograft transplantation in GT-Ko mice are T-cell dependent and can be controlled by co-stimulation blockade.

Original languageEnglish (US)
Pages (from-to)41-47
Number of pages7
JournalAmerican Journal of Transplantation
Volume2
Issue number1
DOIs
StatePublished - Jan 2002

Keywords

  • Anti-CD40L
  • Anti-Gal antibodies
  • CTLA-4lg
  • Galactosyltransferase knock-out
  • Humoral responses
  • Mice
  • Transplantation
  • Xenoantibodies
  • Xenotransplant

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