The effect of CD28/B7 blockade on alloreactive T and B cells after liver cell transplantation

Background. Hepatocyte cell lines are beginning to be developed as universa l donors for isolated liver cell transplantation, which is a less invasive method than orthotopic liver transplantation for treatment of metabolic liv er disease. The immune response to isolated liver cell transplantation and its modification by costimulatory blockade are as yet not well delineated. Methods. Adenovirus expressing CTLA4Ig was used to study blockade of the co stimulatory CD28/B7 pathway in murine models of hepatocyte transplantation, and the effects on alloreactive T and B cells were studied. Results. CTLA4Ig delayed rejection of subcutaneously administered C57L-deri ved murine hepatoma cells in CBA/J recipients for > 50 days. Activation and cytokine secretion by allospecific CD4(+) and CD8(+) T cells were initiall y blocked by CTLA4Ig; delayed rejection was associated with tumor infiltrat ion by CD8+ T cells that did not secrete interferon-gamma, CTLA4Ig failed t o block transplant rejection in primed mice, indicating that memory effecto r T cells were resistant to its action. In contrast, CTLA4Ig suppressed bot h naive and memory alloreactive B cells. High levels of CTLA4fg mediated ac ceptance of hepatoma cells delivered directly into the spleen. However, iso lated primary C57BL/6 mouse hepatocytes delivered into the spleen were reje cted with only moderately delayed kinetics. Conclusions. Transplant antigenicity, transplant site, and CTLA4Ig dose all affected the survival of transplanted liver cells. CD8(+) T cells are sign ificant mediators of hepatocyte transplant rejection and are relatively res istant to costimulatory blockade with CTLA4Ig. Strategies to specifically a ntagonize CD8(+) T cells or to modulate MHC class I expression in associati on with costimulatory blockade by CTLA4Ig may enhance the clinical feasibil ity of transplanting allogeneic hepatocytes.