Selective CD28 blockade attenuates CTLA-4–dependent CD8+ memory T cell effector function and prolongs graft survival

Liu, Danya; Badell, I. Raul; Ford, Mandy L.

doi:10.1172/jci.insight.96378

Cited by 23 publications

(13 citation statements)

References 65 publications

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“…Studies have used therapeutics to target costimulatory molecules; for instance, CTLA-4Ig, which binds CD80 and CD86 and prevents their binding to CD28 and CTLA-4, and anti-CD28 domain antibodies (anti-CD28 dAb) that specifically block CD28 but preserve CTLA-4-mediated coinhibition ( 33 – 35 ). A recent study by Liu et al revealed differential outcomes of graft-specific CD8 + memory T cells upon treatment with CTLA-4 Ig and anti-CD28 dAb in a murine model of skin transplantation ( 36 ). Interestingly, the selective CD28 domain antibodies more potently attenuated graft rejection mediated by memory T cells over CTLA-4 Ig, indicating that CTLA-4 and CD28 are important modulators of memory CD8 + T cell recall responses.…”

Section: Coinhibitory Molecules Limit Recall Potentialmentioning

confidence: 99%

Influence of T Cell Coinhibitory Molecules on CD8+ Recall Responses

2018

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T cell co-signaling molecules play an important role in fine-tuning the strength of T cell activation during many types of immune responses, including infection, cancer, transplant rejection, and autoimmunity. Over the last few decades, intense research into these cosignaling molecules has provided rich evidence to suggest that cosignaling molecules may be harnessed for the treatment of immune-related diseases. In particular, coinhibitory molecules such as programmed-death 1, 2B4, BTLA, TIGIT, LAG-3, TIM-3, and CTLA-4 inhibit T cell responses by counteracting TCR and costimulatory signals, leading to the inhibition of proliferation and effector function and the downregulation of activation and adhesion molecules at the cell surface. While many reviews have focused on the role of coinhibitory molecules in modifying primary CD8+ T cell responses, in this review, we will consider the complex role of coinhibitory molecules in altering CD8+ T cell recall potential. As memory CD8+ T cell responses are critical for protective memory responses in infection and cancer and contribute to potentially pathogenic memory responses in transplant rejection and autoimmunity, understanding the role of coinhibitory receptor control of memory T cells may illuminate important aspects of therapeutically targeting these pathways.

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Section: Coinhibitory Molecules Limit Recall Potentialmentioning

confidence: 99%

Influence of T Cell Coinhibitory Molecules on CD8+ Recall Responses

2018

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“…This result was impaired in the presence of the CTLA-4 blocking antibody, but treatment with CTLA-4Ig in combination with anti-TNF and anti-IFN-γ could rescue graft survival in this memory model. 105 Together these data show that preserving CTLA-4 signaling leads to a decrease in inflammatory cytokine production by memory CD8 + T cells and improved allograft survival. This new therapeutic strategy could help to reduce the contribution of endogenous CD8 memory cells to the inflammatory environment of the transplanted tissue to facilitate allograft tolerance.…”

Section: Selective Cd28 Blockade Can Target Important Cell Subsets mentioning

confidence: 77%

“…This result was impaired in the presence of the CTLA-4 blocking antibody, but treatment with CTLA-4Ig in combination with anti-TNF and anti-IFN-γ could rescue graft survival in this memory model 105. Selective CD28 blockade reduces the ability of alloantigen-specific effector memory cells to produce interferon-γ and TNF, leading to a decreased recruitment of myeloid cells into the graft tissue.…”

mentioning

confidence: 93%

Memory T‐cell exhaustion and tolerance in transplantation

Hartigan

Sun

Ford

2019

Immunological Reviews

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One of the biggest barriers to achieving allograft tolerance is the presence of immunological memory within the recipient, which confers a faster, more robust immune response that is in most cases more resistant to pharmacologic immunosuppression. This review will identify the mechanisms by which alloreactive T cells arise within hosts prior to transplantation, and explore the properties of immunological memory that contribute to allograft rejection. In doing so we will also illuminate how targeting pathways that induce memory T cell exhaustion can promote allograft tolerance.Recent studies demonstrating the impact of the allograft microenvironment on memory cell survival and activation, as well as new therapeutic strategies that are being explored to mitigate memory driven allograft rejection, will also be reviewed. K E Y W O R D Scostimulation blockade, exhaustion, T-cell memory, tolerance, transplant

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“…In contrast, anti-PD-L1 had no effect on the ability of selective CD28 blockade to attenuate donor-reactive memory CD8+ T cell cytokine function. 36…”

Section: Models Of Skin Transplantationmentioning

confidence: 99%

Selective Costimulation Blockade With Antagonist Anti-CD28 Therapeutics in Transplantation

Vanhove¹,

Poirier

Soulillou

et al. 2019

Transplantation

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Nephrotoxicity of calcineurin inhibitors and uncontrolled effector function of alloreactive T lymphocytes are main drivers of transplant dysfunctions. T lymphocytes either directly damage tissues or indirectly promote inflammation and antibody responses. Beside inhibitors of calcium-dependent pathways and anti-metabolites, modulators of T cell costimulation are elected pharmacological tools to enable interference with immune-mediated transplant dysfunctions. CD28 and CTLA-4 are major co-stimulatory and co-inhibitory cell surface signaling molecules interacting with CD80/86, known to be critically important for immune response of committed T cells and regulation. Initial "bench to beside" translation, two decades ago, resulted in the development of belatacept (CTLA4-Ig), a biologic inhibiting interaction of both CD28 and CTLA-4 with CD80/86. Despite proven effectiveness in inhibiting allo-immune responses, clinical use of belatacept in kidney transplantation revealed a substantially high incidence of acute, cell-mediated rejection. The etiology of « belataceptresistant graft rejection » was allocated to elevated pretransplant frequencies of CD28+ memory T cells. Owing to different requirement in CD28 costimulatory and CTLA-4 coinhibitory signals to control naïve and memory T cells, selective antagonists of CD28-CD80/86 interactions have been developed on the rationale that preservation of CTLA4mediated regulatory mechanisms would result in a better control of alloreactivity and would represent a "Treg-compatible" immunosuppression. After the successful testing of selective CD28 antagonists in First In Human studies, this review delineates how this shift in paradigm performed in preclinical transplantation models and evaluates its clinical potential.

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Selective CD28 blockade attenuates CTLA-4–dependent CD8+ memory T cell effector function and prolongs graft survival

Cited by 23 publications

References 65 publications

Influence of T Cell Coinhibitory Molecules on CD8+ Recall Responses

Influence of T Cell Coinhibitory Molecules on CD8+ Recall Responses

Memory T‐cell exhaustion and tolerance in transplantation

Selective Costimulation Blockade With Antagonist Anti-CD28 Therapeutics in Transplantation

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