Layers of regulation in induction of mixed chimerism by anti-CD40L

Lucas, Carrie L.; Sykes, Megan

doi:10.4161/chim.2.4.19053

Cited by 2 publications

(2 citation statements)

References 24 publications

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“…Why is an intact PD-1 pathway apparently required for CD40/CD40L interactions for the development of autoimmune pathology and autoantibody production? In agreement with our results, the ability of anti-CD40L to prolong graft survival was lost after PD-1 blockade (45), and tolerance induction by allogeneic bone marrow transplantation requires an intact PD-1 inhibitory pathway (44, 62). T cell exhaustion, mediated by the PD-1 inhibitory pathway, is reversed after blocking PD-1 or PD-L1.…”

Section: Discussionsupporting

confidence: 91%

Requirement for CD40/CD40L Interactions for Development of Autoimmunity Differs Depending on Specific Checkpoint and Costimulatory Pathways

Voynova¹,

Mahmoud²,

Woods

et al. 2018

ImmunoHorizons

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CD40/CD40L interactions play a critical role in immunity and autoimmunity. In this study, we sought to understand the requirement for CD40 signaling in the programmed cell death-1 (PD-1) checkpoint and CD28 costimulatory pathways important for maintenance of peripheral tolerance. Blocking either pathway can result in loss of self-tolerance and development of autoimmunity. We found that primary Sjögren’s syndrome (pSS) and autoimmune thyroid diseases (ATDs) that develop spontaneously in CD28-deficient IFN-γ −/− NOD.H-2h4 (CD28 −/− ) mice required CD40 signaling. Specifically, blockade of CD40L with the anti-CD40L mAb, MR1, inhibited autoantibody production and inflammation in thyroid and salivary gland target tissues. Unexpectedly, however, ATD and pSS in PD-1–deficient IFN-γ −/− NOD.H-2h4 (PD-1 −/− ) mice developed independently of CD40/CD40L interactions. Treatment with MR1 had no effect and even exacerbated disease development in pSS and ATD, respectively. Most interesting, anti-thyroglobulin and pSS-associated autoantibodies were increased following anti-CD40L treatment, even though MR1 effectively inhibited the spontaneous splenic germinal centers that form in PD-1–deficient mice. Importantly, blockade of the PD-1 pathway by administration of anti–PD-1 mAb in CD28 −/− mice recapitulated the PD-1 −/− phenotype, significantly impacting the ability of MR1 to suppress ATD and pSS in these mice. These results indicate that there can be different pathways and requirements to autoimmune pathogenesis depending on the availability of specific checkpoint and costimulatory receptors, and an intact PD-1 pathway is apparently required for inhibition of autoimmunity by anti-CD40L.

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Section: Discussionsupporting

confidence: 91%

Requirement for CD40/CD40L Interactions for Development of Autoimmunity Differs Depending on Specific Checkpoint and Costimulatory Pathways

Voynova¹,

Mahmoud²,

Woods

et al. 2018

ImmunoHorizons

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“…In that system, NKT cells, IL-4, Tregs, and IL-10 were all necessary for tolerance to develop. Similarly, studies by Sykes and colleagues (52)(53)(54)(55)(56) demonstrated that peripheral mechanisms are critical for the early establishment of tolerance induced by bone marrow transplantation and costimulation blockade. CD8 + T cells undergoing tolerance in that model intrinsically required CTLA-4 and programmed death-1 (PD-1) (55) and the nuclear factor for activation of T cells (NFAT)-1 pathway (56) but also recipient B cells, recipient CD4 + T cells, recipient MHC class II, and recipient dendritic cells (52,53).…”

Section: Cell-intrinsic Mechanisms Of T-cell Transplantation Tolerancmentioning

confidence: 94%

Transplantation tolerance and its outcome during infections and inflammation

Chong

Alegre

2014

Immunological Reviews

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Summary Much progress has been made towards understanding the mechanistic basis of transplantation tolerance in experimental models, which includes clonal deletion of alloreactive T and B cells, induction of cell-intrinsic hyporesponsiveness, and dominant regulatory cells that mediate infectious tolerance and linked-suppression. Despite encouraging success in the laboratory, achieving tolerance in the clinic remains challenging, but the basis for these challenges are beginning to be understood. Heterologous memory alloreactive T cells generated by infections prior to transplantation have been shown to be a critical barrier to tolerance induction. Furthermore, infections at the time of transplantation and tolerance induction provide a pro-inflammatory milieu that alters the stability and function of regulatory T cells as well as the activation requirements and differentiation of effector T cells. Thus infections can result in enhanced alloreactivity, resistance to tolerance induction, and destabilization of the established tolerance state. We speculate that these experimental findings have relevance to the clinic, where infections have been associated with allograft rejection and may be a causal event precipitating the loss of grafts after long-periods of stable operational tolerance. Understanding the mechanisms by which infections prevent and destabilize tolerance can lead to therapies that promote stable lifelong tolerance in transplant recipients.

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Layers of regulation in induction of mixed chimerism by anti-CD40L

Cited by 2 publications

References 24 publications

Requirement for CD40/CD40L Interactions for Development of Autoimmunity Differs Depending on Specific Checkpoint and Costimulatory Pathways

Requirement for CD40/CD40L Interactions for Development of Autoimmunity Differs Depending on Specific Checkpoint and Costimulatory Pathways

Transplantation tolerance and its outcome during infections and inflammation

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