Alefacept promotes co-stimulation blockade based allograft survival in nonhuman primates

Weaver, T.; Charafeddine, Ali H.; Ágarwal, Avinash Kumar; Turner, Alexandra P.; Russell, Maria C.; Leopardi, F.; Kampen, Robert L.; Stempora, Linda; Song, Mingqing; Larsen, Christian; Kirk, Allan D.

doi:10.1038/nm.1993

Cited by 177 publications

(180 citation statements)

References 14 publications

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“…This has broad clinical implications for solid organ transplantation, since Tm generated in response to pathogens can react against alloantigens in a process called heterologous immunity (6). Standard immunosuppressive agents and lymphocyte depleting antibodies have a limited impact on memory cells (7), and the efficacy and safety of new strategies to inhibit Tm by targeting adhesion molecules such as CD2 (8) and LFA-1 (9) remain to be proven. Therefore, innovative and effective strategies to inhibit or deplete Tm are required.…”

Section: Introductionmentioning

confidence: 99%

Bcl-2 Inhibition to Overcome Memory Cell Barriers in Transplantation

Cippà

Gabriel

Kraus

et al. 2014

American Journal of Transplantation

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y Both authors contributed equally.Memory T cells (Tm) represent a major barrier for immunosuppression and tolerance induction after solid organ transplantation. Taking into consideration the critical role of the intrinsic apoptosis pathway in the generation and maintenance of Tm, we developed a new concept to deplete alloreactive Tm by targeting Bcl-2 proteins. The small-molecule Bcl-2/Bcl-XL inhibitor ABT-737 efficiently induced apoptosis in alloreactive Tm in vitro and in vivo and prolonged skin graft survival in sensitized recipients. A short course of ABT-737 induction therapy prevented Tm-mediated resistance in a donor-specific transfusion model and allowed mixed chimerism induction across Tm barriers. Since Bcl-2 inhibitors yielded encouraging safety results in cancer trials, this novel approach might represent a substantial advance to prevent allograft rejection and induce tolerance in sensitized recipients.

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Section: Introductionmentioning

confidence: 99%

Bcl-2 Inhibition to Overcome Memory Cell Barriers in Transplantation

Cippà

Gabriel

Kraus

et al. 2014

American Journal of Transplantation

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“…There was a consensus that memory T cells do not require CD28 costimulation for expansion during secondary responses (2), based on a few studies in vitro with strong and sustained nonphysiological TCR stimulation (3,4) and in vivo models in CD28-deficient mice (5,6) that present abnormal immunity. Some preclinical studies in macaques suggested also that memory T cells promote allograft rejection, particularly in costimulation blockade-based immunosuppressive regimens (7,8). However, in contrast to humans or baboons, CD4 + effector memory T lymphocytes (Tem) of macaques do not express CD28 (9,10) and might show different costimulation requirements for their activation than do human and baboon counterparts.…”

mentioning

confidence: 99%

Selective CD28 Antagonist Blunts Memory Immune Responses and Promotes Long-Term Control of Skin Inflammation in Nonhuman Primates

Poirier

Chevalier

Mary

et al. 2016

The Journal of Immunology

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Novel therapies that specifically target activation and expansion of pathogenic immune cell subsets responsible for autoimmune attacks are needed to confer long-term remission. Pathogenic cells in autoimmunity include memory T lymphocytes that are long-lived and present rapid recall effector functions with reduced activation requirements. Whereas the CD28 costimulation pathway predominantly controls priming of naive T cells and hence generation of adaptive memory cells, the roles of CD28 costimulation on established memory T lymphocytes and the recall of memory responses remain controversial. In contrast to CD80/86 antagonists (CTLA4-Ig), selective CD28 antagonists blunt T cell costimulation while sparing CTLA-4 and PD-L1–dependent coinhibitory signals. Using a new selective CD28 antagonist, we showed that Ag-specific reactivation of human memory T lymphocytes was prevented. Selective CD28 blockade controlled both cellular and humoral memory recall in nonhuman primates and induced long-term Ag-specific unresponsiveness in a memory T cell–mediated inflammatory skin model. No modification of memory T lymphocytes subsets or numbers was observed in the periphery, and importantly no significant reactivation of quiescent viruses was noticed. These findings indicate that pathogenic memory T cell responses are controlled by both CD28 and CTLA-4/PD-L1 cosignals in vivo and that selectively targeting CD28 would help to promote remission of autoimmune diseases and control chronic inflammation.

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“…Currently, alefacept is approved to treat plaque psoriasis. Preclinical studies in nonhuman primates have demonstrated a survival benefit of alefacept, when used in conjunction with costimulatory blockade, but not alone; however in human trials have never shown a benefit (Weaver et al, 2009). Fig.…”

Section: Alefaceptmentioning

confidence: 99%