Inhibition of recall responses through complementary therapies targeting CD8+T-cell- and alloantibody-dependent allocytotoxicity in sensitized transplant recipients

Jason M. Zimmerer, Phillip H. Horne, Lori A. Fiessinger, Mason G. Fisher, Kartika Jayashankar, Sierra F. Garcia, Mahmoud Abdel-Rasoul, Nico van Rooijen, Ginny L. Bumgardner

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5 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1157-1169
Number of pages13
JournalCell transplantation
Volume22
Issue number7
DOIs
StatePublished - 2013

Keywords

  • Alloantibody
  • CD154
  • CD8+ T-cells
  • Hepatocellular transplantation
  • LFA-1
  • Sensitized recipients

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    Zimmerer, J. M., Horne, P. H., Fiessinger, L. A., Fisher, M. G., Jayashankar, K., Garcia, S. F., Abdel-Rasoul, M., van Rooijen, N., & Bumgardner, G. L. (2013). Inhibition of recall responses through complementary therapies targeting CD8+T-cell- and alloantibody-dependent allocytotoxicity in sensitized transplant recipients. Cell transplantation, 22(7), 1157-1169. https://doi.org/10.3727/096368912X657350