Inhibition of Recall Responses through Complementary Therapies Targeting CD8⁺T-Cell- and Alloantibody-Dependent Allocytotoxicity in Sensitized Transplant Recipients

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 which target non-CD8-mediated recall alloimmunity.

Integrins as Therapeutic Targets: Successes and Cancers

“…It reached PH3 trial in the clinic. Although preclinical studies support the efficacy of anti-LFA-1 antibodies in suppressing graft rejection [ 173 , 174 ], Odulimomab development appears to have been terminated.…”

Crosstalk Between T and B Cells in the Germinal Center After Transplantation

“…In transplantation, Bumgardner and colleagues also observed the role of CD8 T cells in alloantibody reduction 70 . In their model, allo-primed CD8 T cells targeted allo-primed B cells via perforin and FasL in a antigen specific manner 71 .…”

Integrins in T Cell Physiology

“…Odulimomab is a chimeric IgG1, which targets αLβ2 to prevent delayed graft function. Although preclinical studies supported the efficacy of the molecule, its development is terminated [ 58 , 59 ]. Rovelizumab is a humanized anti-αL antibody used in phase 3 trial for cerebral ischemia.…”