Alloreactive (CD4-Independent) CD8+ T cells jeopardize long-term survival of intrahepatic islet allografts.
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.
Lunsford
K E
KE
Integrated biomedical Science Graduate Program, College of Medicine and Public Health, The Ohio State University, Columbus, OH, USA.
Jayanshankar
K
K
Eiring
A M
AM
Horne
P H
PH
Koester
M A
MA
Gao
D
D
Bumgardner
G L
GL
D000818:Animals; D018414:CD8-Positive T-Lymphocytes; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006085:Graft Survival / Q000276:immunology*; D022781:Hepatocytes / Q000637:transplantation; D007165:Immunosuppression Therapy; D016381:Islets of Langerhans Transplantation / Q000276:immunology* / Q000379:methods; D051379:Mice