CD28 blockade controls T cell activation to prevent graft-versus-host disease in primates

Watkins, Benjamin; Tkachev, Victor; Furlan, Scott N.; Hunt, Daniel J.; Betz, Kayla; Yu, Alison; Brown, Melanie; Poirier, Nicolas; Zheng, Hengqi; Taraseviciute, Agne; Colonna, Lucrezia; Mary, Caroline; Blancho, Gilles; Soulillou, Jean Paul; Panoskaltsis‐Mortari, Angela; Sharma, Prachi; García, Anapatricia; Strobert, Elizabeth; Hamby, Kelly; Garrett, Aneesah; Deane, Taylor; Blazar, Bruce R.; Vanhove, Bernard; Kean, Leslie S.

doi:10.1172/jci98793

Cited by 45 publications

(64 citation statements)

References 86 publications

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“…The concept has been further assessed in a nonhuman primate acute GVHD model where FR104 was compared with belatacept. Here, 37 in contrast with kidney and heart transplant models, FR104/sirolimus did not lead to an amplification of Treg reconstitution or homeostasis. While combination prophylaxis with FR104/sirolimus initially preserved absolute Treg numbers as well as the Treg/Tconv ratio, this effect was not durable, with peripheral blood Treg counts dropping by approximately day 25 after transplant.…”

Section: Model Of Bone-marrow Transplantationcontrasting

confidence: 64%

“…FR104monoprophylaxis delayed the onset of acute GVHD with a survival advantage, but eventually acute GVHD occurred. Gene set enrichment analysis (GSEA) revealed relative over-and underrepresentation of multiple gene sets in the FR104 monoprophylaxis 37. These included gene sets indicating relative preservation of naive T cells and underrepresentation of gene sets associated with cell proliferation, T cell antigen-dependent activation, and effector differentiation.…”

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confidence: 99%

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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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Section: Model Of Bone-marrow Transplantationcontrasting

confidence: 64%

mentioning

confidence: 99%

Selective Costimulation Blockade With Antagonist Anti-CD28 Therapeutics in Transplantation

Vanhove¹,

Poirier

Soulillou

et al. 2019

Transplantation

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“…Consequently, current therapeutics that solely block CD28 are undergoing testing. 70 Interestingly, the first clinical trial using alefacept to control steroid-resistant GvHD has also proved its efficacy in this disease. [71][72][73] In conclusion, our results reveal that KCs transmit signals through the costimulatory receptors CD58/CD2 and CD54/LFA-1, generating a micromilieu that enables Th1 and Th17 polarization independent of the presence of DCs.…”

Section: Discussionmentioning

confidence: 99%

Keratinocytes costimulate naive human T cells via CD2: a potential target to prevent the development of proinflammatory Th1 cells in the skin

et al. 2019

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The interplay between keratinocytes and immune cells, especially T cells, plays an important role in the pathogenesis of chronic inflammatory skin diseases. During psoriasis, keratinocytes attract T cells by releasing chemokines, while skin-infiltrating selfreactive T cells secrete proinflammatory cytokines, e.g., IFNγ and IL-17A, that cause epidermal hyperplasia. Similarly, in chronic graftversus-host disease, allogenic IFNγ-producing Th1/Tc1 and IL-17-producing Th17/Tc17 cells are recruited by keratinocyte-derived chemokines and accumulate in the skin. However, whether keratinocytes act as nonprofessional antigen-presenting cells to directly activate naive human T cells in the epidermis remains unknown. Here, we demonstrate that under proinflammatory conditions, primary human keratinocytes indeed activate naive human T cells. This activation required cell contact and costimulatory signaling via CD58/CD2 and CD54/LFA-1. Naive T cells costimulated by keratinocytes selectively differentiated into Th1 and Th17 cells. In particular, keratinocyte-initiated Th1 differentiation was dependent on costimulation through CD58/CD2. The latter molecule initiated STAT1 signaling and IFNγ production in T cells. Costimulation of T cells by keratinocytes resulting in Th1 and Th17 differentiation represents a new explanation for the local enrichment of Th1 and Th17 cells in the skin of patients with a chronic inflammatory skin disease. Consequently, local interference with T cell-keratinocyte interactions may represent a novel strategy for the treatment of Th1 and Th17 cell-driven skin diseases.In addition, in chronic graft-versus-host disease (GVHD), a major complication of allogenic stem cell transplantation, the KCmediated secretion of chemokines (CXCL9 and CXCL10) leads to the recruitment of alloreactive T cells into the skin. 14 These allogenic T cells predominantly belong to the IFNγ-producing Th1/ Tc1 and IL-17-producing Th17/Tc17 subpopulations and cause cutaneous manifestations, e.g., follicular erythema. [15][16][17] Although the pivotal role of KCs in non-contact-mediated communication during chronic skin inflammation is quite well understood, the direct interaction between KCs and T cells remains elusive. In particular, the potential of KCs to act as nonprofessional APCs, enabling them to costimulate T cells directly in the skin, is still debated.T cells require two distinct signals for activation and clonal expansion. The first signal is transmitted by the antigen-specific T cell receptor (TCR) on T cells, following recognition of antigenic peptides loaded on MHC class I or class II molecules expressed by APCs. The first signal secures the antigen specificity of the immune reaction. The second signal is transmitted through costimulatory receptors, dictating the progression to T cell activation. Between

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“…They further demonstrated the role of Aurora Kinase A and the OX40:OX40L pathways as novel mediators of aGVHD induced in both the NHP and human alloreactive T cells that can be blocked with the combination of mammalian target of rapamycin inhibition with sirolimus to induce long-term control of both hyperacute and breakthrough aGVHD (39,40). More recently, monoprophylaxis with FR104, an antagonistic CD28-specific pegylated-Fab' , or the combined prophylaxis with sirolomus/FR104 enhanced the control of effector T cell activation and proliferation to control GVHD in NHPs (41). In circulating monocytes in cGVHD compared to monocytes from normal subjects and non-cGVHD, two pathways were upregulated: (1) interferon (IFN) inducible genes (MX1, CXCL9, CXCL10) and innate receptors for cellular damage (Tolllike receptor 7 and DDX58) (42).…”

Section: Profiling Using Transcriptomicsmentioning

confidence: 99%

Biomarkers for Allogeneic HCT Outcomes

et al. 2020

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Allogeneic hematopoietic cell transplantation (HCT) remains the only curative therapy for many hematological malignant and non-malignant disorders. However, key obstacles to the success of HCT include graft-versus-host disease (GVHD) and disease relapse due to absence of graft-versus-tumor (GVT) effect. Over the last decade, advances in "omics" technologies and systems biology analysis, have allowed for the discovery and validation of blood biomarkers that can be used as diagnostic test and prognostic test (that risk-stratify patients before disease occurrence) for acute and chronic GVHD and recently GVT. There are also predictive biomarkers that categorize patients based on their likely to respond to therapy. Newer mathematical analysis such as machine learning is able to identify different predictors of GVHD using clinical characteristics pre-transplant and possibly in the future combined with other biomarkers. Biomarkers are not only useful to identify patients with higher risk of disease progression, but also help guide treatment decisions and/or provide a basis for specific therapeutic interventions. This review summarizes biomarkers definition, omics technologies, acute, chronic GVHD and GVT biomarkers currently used in clinic or with potential as targets for existing or new drugs focusing on novel published work.

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CD28 blockade controls T cell activation to prevent graft-versus-host disease in primates

Cited by 45 publications

References 86 publications

Selective Costimulation Blockade With Antagonist Anti-CD28 Therapeutics in Transplantation

Selective Costimulation Blockade With Antagonist Anti-CD28 Therapeutics in Transplantation

Keratinocytes costimulate naive human T cells via CD2: a potential target to prevent the development of proinflammatory Th1 cells in the skin

Biomarkers for Allogeneic HCT Outcomes

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