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 language | English (US) |
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Pages (from-to) | 1113-1128 |
Number of pages | 16 |
Journal | American Journal of Transplantation |
Volume | 8 |
Issue number | 6 |
DOIs | |
State | Published - 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)