Alloreactive (CD4-independent) CD8+ T cells jeopardize long-term survival of intrahepatic islet allografts

K. E. Lunsford, K. Jayanshankar, A. M. Eiring, P. H. Horne, M. A. Koester, D. Gao, G. L. Bumgardner

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Despite success of early islet allograft engraftment and survival in humans, late islet allograft loss has emerged as an important clinical problem. CD8+ T cells that are independent of CD4+ T cell help can damage allograft tissues and are resistant to conventional immunosuppressive therapies. Previous work demonstrates that islet allografts do not primarily initiate rejection by the (CD4-independent) CD8-dependent pathway. This study was performed to determine if activation of alloreactive CD4-independent, CD8+ T cells, by exogenous stimuli, can precipitate late loss of islet allografts. Recipients were induced to accept intrahepatic islet allografts (islet 'acceptors') by short-term immunotherapy with donor-specific transfusion (DST) and anti-CD154 mAb. Following the establishment of stable long-term islet allograft function for 60-90 days, recipients were challenged with donor-matched hepatocellular allografts, which are known to activate (CD4-independent) CD8+ T cells. Allogeneic islets engrafted long-term were vulnerable to damage when challenged locally with donor-matched hepatocytes. Islet allograft loss was due to allospecific immune damage, which was CD8- but not CD4-dependent. Selection of specific immunotherapy to suppress both CD4- and CD8-dependent immune pathways at the time of transplant protects islet allografts from both early and late immune damage.

Original languageEnglish (US)
Pages (from-to)1113-1128
Number of pages16
JournalAmerican Journal of Transplantation
Volume8
Issue number6
DOIs
StatePublished - Jun 2008

Keywords

  • CD4 T cells
  • CD40 ligand
  • CD8 T lymphocytes
  • Cell-mediated cytotoxicity
  • Cellular transplantation
  • Costimulation blockade
  • Cytotoxic T cells
  • Delayed-type hypersensitivity
  • Donor-specific transfusion
  • Effector mechanisms

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

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