Immune Checkpoints as Therapeutic Targets in Autoimmunity

Paluch, Christopher; Santos, Ana Mafalda; Anzilotti, Consuelo; Cornall, Richard J.; Davis, Simon J.

doi:10.3389/fimmu.2018.02306

Cited by 105 publications

(76 citation statements)

References 90 publications

(89 reference statements)

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“…Agonist antibodies and Fc-fusion proteins that engage co-inhibitory receptors have been successful in treating murine models of autoimmunity. 119 For example, cells from the draining lymph nodes of mice treated with agonistic anti-TIGIT antibodies showed reduced cell proliferation and proinflammatory cytokine production after restimulation with MOG-peptide. Moreover, the severity of EAE was reduced in treated mice accompanied by decreased frequencies of IL-17-producing lymphocytes in the CNS.…”

Section: Therapeutic Induction Of Exhaustion In Autoimmune Diseasesmentioning

confidence: 99%

The yin and yang of co-inhibitory receptors: toward anti-tumor immunity without autoimmunity

Schnell¹,

Bod²,

Madi³

et al. 2020

Cell Res

157

104

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Co-inhibitory receptors are important regulators of T-cell function that define the balance between tolerance and autoimmunity. The immune regulatory function of co-inhibitory receptors, including CTLA-4, PD-1, TIM-3, TIGIT, and LAG-3, was first discovered in the setting of autoimmune disease models, in which their blockade or deficiency resulted in induction or exacerbation of the disease. Later on, co-inhibitory receptors on lymphocytes have also been found to influence outcomes in tumor and chronic viral infection settings. These receptors suppress T-cell function in the tumor microenvironment (TME), thereby making the T cells dysfunctional. Based on this observation, blockade of co-inhibitory receptors (also known as checkpoint molecules) has emerged as a successful treatment option for a number of human cancers. However, severe autoimmune-like side effects limit the use of therapeutics that block individual or combinations of co-inhibitory receptors for cancer treatment. In this review we provide an overview of the role of co-inhibitory receptors in autoimmunity and anti-tumor immunity. We then discuss current approaches and future directions to leverage our knowledge of co-inhibitory receptors to target them in tumor immunity without inducing autoimmunity.

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Section: Therapeutic Induction Of Exhaustion In Autoimmune Diseasesmentioning

confidence: 99%

The yin and yang of co-inhibitory receptors: toward anti-tumor immunity without autoimmunity

Schnell¹,

Bod²,

Madi³

et al. 2020

Cell Res

157

104

View full text Add to dashboard Cite

show abstract

“…Checkpoint molecules regulate T cell activation (Box 5) and conceivably such molecules can be therapeutically modulated in autoimmune diseases [35,36]. The narrow phenotype of gluten-specific CD4 + T cells in CeD includes expression of the inhibitory molecules Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and Programmed death 1 (PD-1) and the stimulatory molecules OX40, CD28 and Inducible T cell COStimulator (ICOS) (Box 3).…”

Section: Targeting Immune Checkpointsmentioning

confidence: 99%

“…Here the mechanism could be to dampen the disease-driving T cell response. Agonists of inhibitory checkpoint molecules have shown efficacy in different autoimmune mouse models [36]. The CTLA-4-Fc-fusion protein Abatacept, which probably acts by outcompeting the CD28:CD80/CD86 binding, serves as an indirect antagonist of this stimulatory checkpoint molecules.…”

Section: Targeting Immune Checkpointsmentioning

confidence: 99%

Therapeutic and Diagnostic Implications of T Cell Scarring in Celiac Disease and Beyond

Christophersen

Risnes

Dahal‐Koirala

et al. 2019

Trends in Molecular Medicine

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Few therapeutic and diagnostic tools specifically aim at T cells in autoimmune disorders, but are T cells a narrow target in these diseases? Lessons may be learned from celiac disease (CeD), one of the few autoimmune disorders where the T cell driving antigens are known, i.e. dietary gluten proteins. T cell clonotypes specific to gluten are expanded, persist for decades and express a distinct phenotype in CeD patients. Cells with this phenotype are increased also in other autoimmune conditions. Accordingly, disease-specific CD4 + T cells form an immunological scar in CeD and probably other autoimmune disorders. We discuss approaches how such T cells may be targeted for better treatment and diagnosis via their antigen specificity or via their expression of characteristic phenotypic markers.

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“…It was postulated that these polymorphisms affect receptor signaling and may be associated with ABDs susceptibility. Recent investigative efforts included the identification of mutations in genes encoding immunological molecules and their possible associations with pathological autoimmune response in various dermatoses [10,25]. Previous reports indicated that CD32B polymorphisms may be associated with systemic lupus erythematosus [26].…”

Section: Discussionmentioning

confidence: 99%

A Comparative Analysis of CD32A and CD16A Polymorphisms in Relation to Autoimmune Responses in Pemphigus Diseases and Subepithelial Autoimmune Blistering Disorders

Gornowicz‐Porowska

Kowalczyk

Seraszek‐Jaros

et al. 2020

Genes

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Autoimmune blistering dermatoses (ABDs) are characterized by autoantibodies to keratinocyte surface antigens and molecules within the dermal–epidermal junction causing disruption of skin integrity. The affinity of Fc receptors (FcRs) causing an autoimmune response in ABDs may vary based on single-nucleotide polymorphisms (SNPs) in FcRs determining the course of disease. This study aimed to explore the effects of CD16A and CD32A SNPs on the autoimmune response in several ABDs. In total, 61 ABDs patients were investigated. ELISA tests, direct immunofluorescence (DIF), TaqMan SNP Genotyping Assays, and statistical analyses were performed. The CA genotype (composed of allele C and A) of rs396991 in CD16A had a higher affinity for tissue-bound IgG1 in pemphigus and for C3 in subepithelial ABDs, showing statistical significance. The greatest relative risk (odds ratio) was reported for AA (rs396991 of CD16A) and CC (rs1801274 of CD32A) homozygotes. There were no statistically significant differences between certain genotypes and specific circulating autoantibodies (anti-DSG1, anti-DSG3 IgG in pemphigus; anti-BP180, anti-BP230 IgG) in subepithelial ABDs. Our findings indicated that rs396991 in CD16A may be of greater importance in ABDs development. Moreover, FcR polymorphisms appeared to have a greater impact on tissue-bound antibodies detected using DIF than circulating serum antibodies in ABDs.

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Immune Checkpoints as Therapeutic Targets in Autoimmunity

Cited by 105 publications

References 90 publications

The yin and yang of co-inhibitory receptors: toward anti-tumor immunity without autoimmunity

The yin and yang of co-inhibitory receptors: toward anti-tumor immunity without autoimmunity

Therapeutic and Diagnostic Implications of T Cell Scarring in Celiac Disease and Beyond

A Comparative Analysis of CD32A and CD16A Polymorphisms in Relation to Autoimmune Responses in Pemphigus Diseases and Subepithelial Autoimmune Blistering Disorders

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