Inhibition of Recall Responses through Complementary Therapies Targeting CD8+ T-Cell- and Alloantibody-Dependent Allocytotoxicity in Sensitized Transplant Recipients. Issue 7 (July 2013)

• Record Type: Journal Article
• Authors: Zimmerer, Jason M.; Horne, Phillip H.; Fiessinger, Lori A.; Fisher, Mason G.; Jayashankar, Kartika; Garcia, Sierra F.; Abdel-Rasoul, Mahmoud; Van Rooijen, Nico; Bumgardner, Ginny L.
• Is Part Of: Cell transplantation. Volume 22:Issue 7(2013)
• Page Start: 1157
• Page End: 1169
• Publication Date: 2013-07
• Subjects: Alloantibody -- CD154 -- CD8+ T-cells -- Hepatocellular transplantation -- LFA-1 -- Sensitized recipients; Cell transplantation -- Periodicals; Cell Transplantation; Cell transplantation; Electronic journals; Periodicals; Periodicals; 571.638
• DOI: 10.3727/096368912X657350
• Languages: English
• ISSNs: 0963-6897

Abstract

Allospecific T memory cell responses in transplant recipients arise from environmental exposure to previous transplantation or cross-reactive heterologous immunity. Unfortunately, these memory responses pose a significant barrier to the survival of transplanted tissue. We have previously reported that concurrent inhibition of CD154 and LFA-1 suppresses primary CD8-dependent rejection responses that are not controlled by conventional immunosuppressive strategies. We hypothesized that CD154- and LFA-1-mediated inhibition, by targeting activation as well as effector functions, may also be efficacious for the control of alloreactive CD8 + T-cell responses in sensitized hosts. We found that treatment with anti-LFA-1 mAb alone enhanced transplant survival and reduced CD8-mediated cytotoxicity in sensitized CD4 KO recipients. However, treatment with anti-CD154 mAb alone did not have an effect. Notably, when both CD4- and CD8-dependent rejection pathways are operative (wild-type sensitized recipients), LFA-1 significantly inhibited CD8-mediated in vivo allocytotoxicity but did not correspond with enhanced hepatocyte survival. We hypothesized that this was due to alloantibody-mediated rejection. When anti-LFA-1 mAb treatment was combined with macrophage depletion, which we have previously reported impairs alloantibody-mediated parenchymal cell damage, in vivo cytotoxic effector function was significantly decreased and was accompanied by significant enhancement of hepatocyte survival in sensitized wild-type recipients. Therefore, LFA-1 is a potent therapeutic target for reduction of CD8-mediated cytotoxicity in sensitized transplant recipients and can be combined with other treatments that target non-CD8-mediated recall alloimmunity.