For example, a LAG-3 agonistic antibody was able to inhibit T cell proliferation only when co-crosslinked with the TCR by a secondary antibody (83)

For example, a LAG-3 agonistic antibody was able to inhibit T cell proliferation only when co-crosslinked with the TCR by a secondary antibody (83). how understanding these processes might shape the design of more effective therapeutic brokers in future. gene are associated with susceptibility to a variety of autoimmune conditions including systemic lupus erythematosus (10), atopy and rheumatoid arthritis (11, 12), and progression in multiple sclerosis (MS) (13). It is in fact possible that the therapeutic benefit of interferon-beta in MS may be due to it upregulating PDL1 expression on myeloid cells (14). Furthermore, autoantibodies against PDL1 have been found in patients with rheumatoid arthritis and correlate with disease activity (15). In addition to PD1 and CTLA4 there are numerous other immune checkpoint receptors that have been shown to have important immune regulatory function. B- and T-lymphocyte attenuator (BTLA) knock-out mice gradually develop multi-organ inflammatory infiltrates and a hepatitis-like disease (16), whilst a gene polymorphism in humans is associated with rheumatoid arthritis (17). Mice lacking T cell Immunoreceptor with Ig and ITIM domains (TIGIT) do not develop spontaneous autoimmunity but have increased susceptibility to experimental autoimmune encephalitis (EAE) (18). Similarly, mice without Lymphocyte-activation gene 3 (LAG3) do not develop spontaneous disease but have accelerated diabetes onset when bred onto a NOD background. Polymorphisms of the T cell immunoglobulin and mucin domain name 3 (TIM-3) receptor in humans have been associated with MS (19), rheumatoid arthritis (20) and ankylosing spondylitis (21). Rationale for targeting immune checkpoints in autoimmunity The association of immune checkpoint receptors with autoimmunity in humans and the autoimmune phenomena seen when these receptors are knocked out in experimental mice or blocked therapeutically in patients all offer evidence of the hSNFS crucial role these pathways play in regulating immune responses. It also raises the possibility that inducing signaling through these receptors could switch off detrimental immune responses and drive the immune system back toward a state of tolerance after control has been lost in autoimmune disease. This idea has been explored for a range of different targets and in multiple mouse models of autoimmunity (summarized in Desidustat Table ?Table1).1). Below we will review attempts that have been made to date to produce agonistic compounds capable of delivering inhibitory signals to T cells through checkpoint receptors. Such inhibitory agonists, if they could be translated into human disease, would comprise a new, broadly useful class of Desidustat immunosuppressive drug (see Table ?Table2:2: Summary of key points). Table 1 Checkpoint agonists that have shown efficacy in treating mouse models of autoimmunity. CIADSS/T cell colitis(22)(23)(24)hPDL1-hIgG4 Fc fusionIslet transplant(25)PDL1 transfected dendritic cellsEAE(26)BTLAmHVEM-mIgG1 Fc fusionGVHD(27)mHVEM-hIgG1 Fc fusionCardiac allograft(28)Hamster IgG antibody(clone 6A6)GVHD(29)Rat IgG antibody(clone Byk-1)GVHD(30)TIGITArmenian hamster IgG antibody (4D4)EAE(31)TIM-3Galectin 9EAE,Cardiac allograft,Skin allograft,CIA(32)(33)(34)(35)CD200 ReceptormCD200-mIgG2amutCIACIARat islet xenograft(36)(37)(38)mCD200-mIgG2aEAE(39)Rat IgG1 antibody(clone OX110)CIAInfluenza contamination(40)(41)Rat IgG1 antibody(clone DX109)Autoimmune uveoretinitis(42)DNA aptamersSkin graft(43)CD200R/Inhibitory: CD160TIGIT (T cell Immunoreceptor with Ig and ITIM domains)CD155, CD112Activating: CD226Inhibitory: CD96CD200 Receptor (CD200R1)CD200Activating: CD200R2-5 (mice only, not expressed in humans)TIM-3 (T cell immunoglobulin and mucin domain name 3)Galectin 9, HMGB1, Phosphatidylserine, CEACAM-1NumerousLAG-3 (Lymphocyte-activation gene 3)MHC Class IIActivating: T cell receptor, CD4VISTA (V-domain Ig suppressor of T cell activation)Unknown (VISTA may Desidustat also serve as a co-inhibitory ligand for an, as yet, unidentified receptor)C Open in a separate windows Agonist antibodies In contrast to natural ligands, therapeutic antibodies can be produced which have specificity for only the inhibitory partner in paired receptor systems, avoiding the risk of inducing counterproductive signaling through activating receptors. Antibodies can also be selected with many-fold higher affinity for their cognate receptor than the affinity of the endogenous receptor-ligand conversation. Furthermore, the significant precedent for monoclonal antibodies to be used as therapeutics in humans, could mean that translation to the medical center will face fewer difficulties than would be encountered by novel Fc-fusions or other innovative constructs. It was demonstrated long ago in the context of the activating co-stimulatory receptor CD28, that antibodies could substitute for natural ligands, and in fact could deliver a far more potent signal.

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