specific parasite peptides to promote a systemic immunosuppressive Th2 environment [28].
Oral Tolerance
Ingestion of antigens leads to absorption and interaction with the reticuloendothelial system of the liver. Repeated ingestion can result in oral tolerance, defined as the inability to respond to the ingested antigen when given parenterally [29]. Low doses of antigen induce iTregs, while higher doses create anergic tolerance. Studies involving the induction of oral tolerance to glutamic acid decarboxylase, the instigating autoantigen in T1DM, are ongoing. The applicability of oral tolerance depends on identification of disease‐specific initiating autoantigens; thus, it would be currently relevant in AILDs only for PBC and type 2 AIH.
Strategies to Treat Established Autoimmune Diseases
At the time of diagnosis, the initiating events of most autoimmune diseases likely occurred months to years earlier and mechanisms of perpetuation are well established. This poses challenges for clinical management and focuses attention on therapeutic strategies to control inflammation, modify symptoms and signs, and retard progression. Progress in understanding the pathogenesis of autoimmune diseases provides rationales for additional conventional and novel therapies (Table 2.3). Two therapeutic approaches warrant additional comment.
Inducible T Regulatory T Cells
Studies of two strategies to produce iTregs specific for autoantigens are in progress (Table 2.3) [1]. The first strategy is to increase the proliferation of existing iTreg populations by infusion of low doses of IL‐2, which is being studied in hematopoietic stem cell transplantation, graft‐versus‐host disease, T1DM, HCV‐associated vasculitis, and SLE. The second strategy involves generating antigen‐specific iTregs from peripheral blood mononuclear cells ex vivo for infusion. iTregs specific for CYP2D6 autoantigens in type 2 AIH have been produced, but not yet infused.
Epigenetic Enhancer Regulation
SNPs within enhancers, especially SEs, play dominant roles in autoimmune pathogenesis (see section Epigenetics) [16]. The theoretical fear that targeting epigenetic regulatory proteins might cause severe toxicity has not been observed with first‐generation inhibitors. Among SE proteins regulating genes associated with activation, stress and differentiation, the bromodomain and extra‐terminal (BET) family has emerged as a prime target for inhibition. BET inhibition decreased macrophage expression of inflammatory genes induced by lipopolysaccharide by preferentially inhibiting de novo expression of SE genes. BET inhibitors also blocked de novo SE gene expression in endothelial cells, markedly reduced CD4 Th cells differentiation to polarized subsets, and prevented effector cytokine production by already polarized Th cells. BET inhibitors also impacted B cells by inhibiting proliferation and ability to switch the isotype of their antibodies. More importantly, BET inhibitors have reduced inflammation and protected from disease in animal models of T1DM, MS, RA, and psoriasis. These data indicate that BET‐specific, and more generally SE‐related, mechanisms are promising therapeutic targets.
Table 2.3 Current and future therapeutic approaches to control autoimmune diseases.
| Approaches | Goal | Status | |
| Increase regulatory control of autoimmune responses | Infuse low‐dose IL‐2 | Expand existing autoantigen‐specific iTregs in vivo | POC established. Clinical trials ongoing |
| Infuse iTregs generated ex vivo to control Th cell and cytokine responses | Ex vivo generation of disease and autoantigen‐specific iTregs | POC of iTreg generation established. No infusion trials to date. Viability, function and distribution after infusion unknown | |
| Bromodomain and extra‐terminal (BET) family of proteins | Inhibit disease‐specific epigenetic enhancers, super enhancers and eRNA production | POC established. Clinical trials ongoing | |
| Mesenchymal stem cells | Inhibit innate immune cells, effector T cells. Induction of iTregs. Reduction of proinflammatory TNF‐α | POC established. Clinical trials ongoing | |
| Decrease numbers and/or functions of autoimmune effector cells and pathogenic autoantibodies | Immunosuppressive drugs: CNI, mTOR, antiproliferative agents | Reduce functional mass of activated T cells using immunosuppressive drugs | SOC in multiple autoimmune diseases. Active research to refine target specificity and reduce toxicities. Combinations of drugs working at different sites of action using subtoxic doses preferred |
| Anti‐CD20 | B‐cell depletion | SOC and off‐label uses | |
| Anti‐BAFF | Initial B‐cell depletion followed by mobilization of memory B cells. Concurrent inhibition of BAFF signaling in T cells | SOC in SLE. Broad future potential, especially in combination regimens | |
| Anti‐BAFF, followed by anti‐CD20 | Depletion of memory B cells mobilized by anti‐BAFF | Sequential use to eliminate mobilized memory B cells to increase efficacy | |
| Anti‐CD40 | Block CD40–CD40L (CD154) costimulation of T cells and B cells | POC. Clinical trial initiated in transplantation | |
| Block IgG recycling and increase IgG clearance | First in class antibody fragment to block FcRn (efgartigimod) | POC to reduce pathogenic autoantibodies and formation of immunoglobulin–autoantigen complexes | |
| Prevent egress of activated T cells from lymph nodes | Block sphingosine‐1‐phosphate receptors | SOC in MS, new agents in development | |
| MDSCs | Inhibit activation and proliferation of autoreactive T cells | POC in preclinical models. Plans for clinical trials in RA | |
| Decrease proinflammatory cytokines | Anti‐TNF‐α or TNF‐α receptor | Decrease TNF‐α mediated tissue injury and proinflammatory signaling | SOC in multiple autoimmune diseases |
| Anti‐IL‐6 or anti‐IL‐6R | Decrease pathological consequences of proinflammatory IL‐6 signaling in innate and adaptive immune response | SOC in RA, clinical trials ongoing | |
| Anti‐IL‐12 | Decrease pathological consequences of proinflammatory IL‐12 signaling in innate and adaptive immune response |
Monoclonal antibody against p40 subunit. SOC in psoriasis and
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