Role of the ICOS-B7h Costimulatory Pathway in the Pathophysiology of Chronic Allograft Rejection

Kashizuka, Hisanori; Sho, Masayuki; Nomi, Takeo; Ikeda, Naoya; Kuzumoto, Yukiyasu; Akashi, Satoru; Tsurui, Yoshikazu; Mizuno, Takashi; Kanehiro, Hiromichi; Yagita, Hideo; Nakajima, Yoshiyuki; Sayegh, Mohamed H.

doi:10.1097/01.tp.0000161665.35243.21

Cited by 28 publications

(20 citation statements)

References 25 publications

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“…More recent studies have confirmed that Fc-mediated T-cell depletion plays a critical role in the effects of CD154-specific antibody, particularly in stringent transplant settings (23). Importantly, however, trials using CD154-specific antibody in humans identified thromboembolic side effects (24 (28,29), however these have all been obtained in less stringent models such as a cardiac transplantation model (29) or using the adoptive transfer of responder T cells (28). Interestingly, an earlier study by Cobbold et al (30) prolonged survival of skin transplants by presensitized mice, however the mechanism responsible for the efficacy of this treatment, a combination of depleting, followed by nondepleting CD4-and CD8-specific antibodies, remains unclear (30 (35,36).…”

Section: Discussionmentioning

confidence: 99%

An Antibody Combination That Targets Activated T Cells Extends Graft Survival in Sensitized Recipients

Greenlaw

Gardner

Farrar

et al. 2008

American Journal of Transplantation

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†The authors contributed equally to this work.Memory T cells are the very essence of adaptive immunity with their rapid and efficient response to antigen rechallenge and long-term persistence. However, it is becoming increasingly evident that when primed with self or transplanted tissue, these cells play a key role in causing and perpetuating tissue damage. Furthermore, current treatments, which efficiently control the naive response, have limited effects on primed T cells. We have used a treatment based on a combination of antibodies specific for molecules expressed by activated T lymphocytes to selectively remove these cells. This approach, which we termed multi-hit therapy, leads to cumulative binding of antibodies to the target T cells and a striking prolongation of skin graft survival in presensitized recipients in a stringent skin transplant model. The findings are consistent with the depletion of graft-specific CD4+ and CD8+ T cells, although other modes of action, such as T-cell regulation and altered migration could play a role. In conclusion, our therapeutic strategy controls primed T cells which are a major driving force in the pathology of many autoimmune diseases and in transplant rejection.

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Section: Discussionmentioning

confidence: 99%

An Antibody Combination That Targets Activated T Cells Extends Graft Survival in Sensitized Recipients

Greenlaw

Gardner

Farrar

et al. 2008

American Journal of Transplantation

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“…ICOS-B7h blockade prolongs allograft survival in several transplantation models (3)(4)(5)(6)(7)(8)(9). Those studies indicate a key role for the ICOS-B7h pathway in acute and chronic rejection and demonstrate the potential use of anti-ICOS therapy in combination with other immunosuppressive agents or other T cell costimulatory blockade regimens to promote allograft survival (3)(4)(5)(6)(7)(8)(9).…”

Section: A Novel Alloantigen-specific Cd8mentioning

confidence: 96%

“…Those studies indicate a key role for the ICOS-B7h pathway in acute and chronic rejection and demonstrate the potential use of anti-ICOS therapy in combination with other immunosuppressive agents or other T cell costimulatory blockade regimens to promote allograft survival (3)(4)(5)(6)(7)(8)(9). However, the exact mechanisms of action of ICOS-B7h blockade in vivo remain unclear.…”

Section: A Novel Alloantigen-specific Cd8mentioning

confidence: 99%

A Novel Alloantigen-Specific CD8+PD1+ Regulatory T Cell Induced by ICOS-B7h Blockade In Vivo

Izawa

Yamaura

Albin

et al. 2007

The Journal of Immunology

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Delayed ICOS-B7h signal blockade promotes significant prolongation of cardiac allograft survival in wild-type but not in CD8-deficient C57BL/6 recipients of fully MHC-mismatched BALB/c heart allografts, suggesting the possible generation of CD8+ regulatory T cells in vivo. We now show that the administration of a blocking anti-ICOS mAb results in the generation of regulatory CD8+ T cells. These cells can transfer protection and prolong the survival of donor-specific BALB/c, but not third party C3H, heart grafts in CD8-deficient C57BL/6 recipients. This is unique to ICOS-B7h blockade, because B7 blockade by CTLA4-Ig prolongs graft survival in CD8-deficient mice and does not result in the generation of regulatory CD8+ T cells. Those cells localize to the graft, produce both IFN-γ and IL-4 after allostimulation in vitro, prohibit the expansion of alloreactive CD4+ T cells, and appear to mediate a Th2 switch of recipient CD4+ T cells after adoptive transfer in vivo. Finally, these cells are not confined to the CD28-negative population but express programmed death 1, a molecule required for their regulatory function in vivo. CD8+PD1+ T cells suppress alloreactive CD4+ T cells but do not inhibit the functions by alloreactive CD8+ T cells in vitro. These results describe a novel allospecific regulatory CD8+PD1+ T cell induced by ICOS-B7h blockade in vivo.

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“…B7RP-1 ligation with ICOS-Ig treatment was found to decrease B7 expression on antigen presenting cells (APCs) in vivo , potentially accounting for these results. Additionally, administration of ICOS blockade in an early or delayed fashion produced dichotomous results, with results favoring delayed ICOS blockade (19–21). To date, there are no published studies testing ICOS pathway blockade in a large animal model.…”

Section: Introductionmentioning

confidence: 99%

A Pilot Trial Targeting the ICOS–ICOS-L Pathway in Nonhuman Primate Kidney Transplantation

Anderson

Song

et al. 2015

American Journal of Transplantation

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Costimulation blockade with the B7-CD28 pathway-specific agent belatacept is now used in clinical kidney transplantation, but its efficacy remains imperfect. Numerous alternate costimulatory pathways have been proposed as targets to synergize with belatacept, one of which being the inducible costimulator (ICOS)-ICOS ligand pathway. Combined ICOS-ICOS-L and CD28-B7 blockade has been shown to prevent rejection in mice, but has not been studied in primates. We therefore tested a novel ICOS-Ig human Fc-fusion protein in a nonhuman primate kidney transplant model alone and in combination with belatacept. ICOS-Ig did not prolong rejection-free survival as a monotherapy or in combination with belatacept. In ICOS-Ig alone treated animals, most graft-infiltrating CD4+ and CD8+ T cells expressed ICOS, and ICOS+ T cells were present in peripheral blood to a lesser degree. Adding belatacept reduced the proportion of graft-infiltrating ICOS+ T cells and virtually eliminated their presence in peripheral blood. Graft-infiltrating T cells in belatacept-resistant rejection were primarily CD8+CD28−, but importantly, very few CD8+CD28− T cells expressed ICOS. We conclude that ICOS-Ig, alone or combined with belatacept, does not prolong renal allograft survival in nonhuman primates. This may relate to selective loss of ICOS with CD28 loss.

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Role of the ICOS-B7h Costimulatory Pathway in the Pathophysiology of Chronic Allograft Rejection

Abstract: These data suggest that the ICOS-B7h pathway is critical in the activation of effector/memory T cells that are necessary for the progression of chronic rejection and provide the rationale to develop novel and specific therapies to prevent this process.

Cited by 28 publications

References 25 publications

An Antibody Combination That Targets Activated T Cells Extends Graft Survival in Sensitized Recipients

An Antibody Combination That Targets Activated T Cells Extends Graft Survival in Sensitized Recipients

A Novel Alloantigen-Specific CD8+PD1+ Regulatory T Cell Induced by ICOS-B7h Blockade In Vivo

A Pilot Trial Targeting the ICOS–ICOS-L Pathway in Nonhuman Primate Kidney Transplantation

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