Finally, CTLA4Ig graduates to the clinic

Sayegh, Mohamed H.

doi:10.1172/jci6952

Cited by 61 publications

(35 citation statements)

References 28 publications

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“…9,16 Indeed, the efficacy of CTLA4Ig therapy has already been proven clinically in the autoimmune disease psoriasis vulgaris. [17][18][19] Phase I-II studies are underway with CTLA4Ig, humanized anti-B7, and anti-CD154 monoclonal antibodies (mAbs) in transplantation and autoimmunity.…”

Section: Discussionmentioning

confidence: 99%

New Insights Into the Interactions Between T-Cell Costimulatory Blockade and Conventional Immunosuppressive Drugs

et al. 2002

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ObjectiveTo determine the precise in vivo interaction between T-cell costimulatory blockade and conventional immunosuppression in transplantation. Summary Background DataBlocking B7 or CD154 T-cell costimulatory activation pathways prevents allograft rejection in small and large animal transplant models and is considered a promising strategy for clinical organ transplantation. MethodsA fully MHC-mismatched vascularized mouse cardiac allograft model was used to test the interactions between anti-CD154 or CTLA4Ig monotherapy and conventional immunosuppressive drugs in promoting long-term graft acceptance. The frequency of alloreactive T cell was measured by ELISPOT. Chronic rejection was examined by histology. ResultsCyclosporine, tacrolimus, and anti-IL-2R monoclonal antibody therapy abrogated the effect of a single-dose protocol of anti-CD154 therapy. In contrast, rapamycin acted synergistically with anti-CD154 therapy in promoting long-term allograft survival. The addition of calcineurin inhibitors did not abolish this synergistic effect. Intense CD154-CD40 blockade by a multiple-dose schedule of anti-CD154 resulted in long-term graft survival and profound alloreactive T-cell unresponsiveness and overcame the opposite effects of calcineurin inhibitors. CTLA4Ig induced long-term graft survival, and the effect was not affected by the concomitant use of any immunosuppressive drugs. ConclusionsThe widespread view that calcineurin inhibitors abrogate the effects of T-cell costimulatory blockade should be revisited. Sufficient costimulatory blockade and synergy induced by CD154 blockade and rapamycin promote allograft tolerance and prevent chronic rejection.

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Section: Discussionmentioning

confidence: 99%

New Insights Into the Interactions Between T-Cell Costimulatory Blockade and Conventional Immunosuppressive Drugs

et al. 2002

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“…Furthermore, our data support the notion that in the absence of CD28 costimulation, a negative regulatory signal provided by interaction of B7-1 with CTLA4 predominates. Since strategies to block CD28-B7 T-cell costimulation are being tested currently in a variety of autoimmune diseases in humans (66), one needs to be aware of the conditions and mechanisms whereby an autoimmune response may occur even in the absence of CD28 costimulation. Therefore, our results have relevant clinical implications for treatment of autoimmune diseases with agents that block costimulatory signals.…”

Section: Discussionmentioning

confidence: 99%

CD28-independent induction of experimental autoimmune encephalomyelitis

Chitnis

Najafian²,

Abdallah³

et al. 2001

J. Clin. Invest.

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Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated disease initiated by antigenspecific CD4 + T cells. Signaling through CD28 is a critical second signal for activation of T cells, and CD28 knockout (CD28KO) mice have been reported to be resistant to induction of EAE. We now report that CD28KO mice have no intrinsic defect in mediating disease, because they developed EAE after passive transfer of primed T cells. After immunization, peripheral T cells from CD28KO mice were primed and developed memory phenotype, but had decreased antigen-specific IFN-γ production as compared with cells from wild-type (WT) animals. Reimmunization of CD28KO mice brought out clinical disease and increased IFN-γ production in vitro. Pathologically, there were cellular infiltrates in the central nervous system, in contrast to single-immunized mice. We show furthermore that blocking B7-1 or CTLA4, but not B7-2, in CD28KO mice induces disease after a single immunization. Thus, EAE can be induced in animals lacking CD28-dependent costimulation, suggesting that alternative costimulatory pathways were used. Blocking the OX40-OX40L costimulatory pathway differentially affected disease induction in CD28KO mice as compared with WT controls. Our data show that EAE may develop in the absence of CD28 T-cell costimulation. These findings have implications for therapies aimed at blocking costimulatory signals in autoimmune diseases.

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“…10 Because of its dominant role in modulating T-cell activation, CTLA-4 has received considerable attention as a therapeutic agent in a variety of in vivo immune responses, including induction of transplantation tolerance. 11 The chimeric CTLA-4-immunoglobulin (CTLA-4-Ig) protein, 12 interferes with T-cell/APC interaction both in vitro and in vivo, preventing xenograft rejection 13 and prolonging allograft survival. 14 In contrast to strategies that interfere with the costimulatory CD28-CD80/CD86 pathway, the availability of reagents that completely abolish T-cell activation by targeting the CTLA-4 molecule might have important clinical implications.…”

Section: Introductionmentioning

confidence: 99%