Many therapies for autoimmune and inflammatory diseases involve the use of nonspecific immune-modulating or immunosuppressive agents such as glucocorticoids or cytotoxic drugs. The goal of development of new treatments for immune-mediated diseases is to design ways to specifically interrupt pathologic immune responses, leaving nonpathologic immune responses intact. Novel ways to interrupt pathologic immune responses that are under investigation include the use of anti-inflammatory cytokines or specific cytokine inhibitors as anti-inflammatory agents, the use of monoclonal antibodies against T or B lymphocytes as therapeutic agents, the use of intravenous Ig for certain infections and immune complex–mediated diseases, the use of specific cytokines to reconstitute components of the immune system, and bone marrow transplantation to replace the pathogenic immune system with a more normal immune system. CTLA-4 inhibitors such as ipilimumab and tremelimumab and anti-PD-1 antibodies such as nivolumab are termed checkpoint inhibitors and have been shown to reverse CD8 T-cell exhaustion in melanoma and other solid tumors and induce immune cell control of tumor growth. A technique that engineers autologous T cells to express antibody receptors that target leukemic cells, termed chimeric antigen receptor T cells (CAR T cells), has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of certain types of leukemias and lymphomas.

Cell-based therapies have been studied for many years, including ex vivo activation of NK cells for reinfusion into patients with malignancies and DC therapy of ex vivo priming of DCs for enhanced presentation of cancer antigens, with reinfusion of primed DCs into the patient. One such strategy for DC therapy has been approved by the FDA for treatment of advanced prostate cancer.

Cytokines and Cytokine Inhibitors Several TNF inhibitors are used as biological therapies in the treatment of rheumatoid arthritis; these include monoclonal antibodies, TNF-R Fc fusion proteins, and Fab fragments. Use of anti-TNF-α antibody therapies such as adalimumab, infliximab, and golimumab has resulted in clinical improvement in patients with these diseases and has opened the way for targeting TNF-α to treat other severe forms of autoimmune and/or inflammatory disease. Blockage of TNF-α has been effective in rheumatoid arthritis, psoriasis, Crohn’s disease, and ankylosing spondylitis. Other cytokine inhibitors are recombinant soluble TNF-α receptor (R) fused to human Ig and anakinra (soluble IL-1 receptor antagonist, or IL-1ra).

TNF-αR-Fc fusion protein (etanercept) and IL-1ra act to inhibit the activity of pathogenic cytokines in rheumatoid arthritis, i.e., TNF-α and IL-1, respectively. Similarly, anti-IL-6, IFN-β, and IL-11 act to inhibit pathogenic proinflammatory cytokines. Anti-IL-6 (tocilizumab) inhibits IL-6 activity, whereas IFN-β and IL-11 decrease IL-1 and TNF-α production. Of particular note has been the successful use of IFN-γ in the treatment of the phagocytic cell defect in chronic granulomatous disease.

TH 17 CD4 T cells have been implicated in the pathogenesis of psoriasis, ulcerative colitis, and other autoimmune diseases. Monoclonal anti bodies have now been developed that target cytokines (IL-12, IL-23) that induce TH 17 T-cell differentiation and are licensed by the FDA for treatment of psoriasis and inflammatory bowel disease. Monoclonal antibodies that directly target IL-17 have also recently been licensed for psoriasis and psoriatic arthritis treatment. Monoclonal antibodies against cytokines and immunoregulatory molecules are now mainstays of cancer and autoimmune disease therapy.

Intravenous Immunoglobulin (IVIg) IVIg has been used successfully to block reticuloendothelial cell function and immune complex clearance in various immune cytopenias such as immune thrombocytopenia. In addition, IVIg is useful for prevention of tissue damage in certain inflammatory syndromes such as Kawasaki disease and as Ig replacement therapy for certain types of immunoglobulin deficiencies. In addition, controlled clinical trials support the use of IVIg in selected patients with graft-versus-host disease, multiple sclerosis, myasthenia gravis, Guillain-Barré syndrome, and chronic demyelinating polyneuropathy.

Stem Cell Transplantation Hematopoietic stem cell transplantation (SCT) is now being studied to treat several autoimmune diseases including systemic lupus erythematosus, multiple sclerosis, and scleroderma. The goal of immune reconstitution in autoimmune disease syndromes is to replace a dysfunctional immune system with a normally reactive immune cell repertoire. Controlled clinical trials in these three diseases are now being launched in the United States and Europe to compare the toxicity and efficacy of conventional immunosuppression therapy with that of myeloablative autologous SCT. Recently, SCT was used in the setting of HIV-1 infection. HIV-1 infection of CD4+ T cells requires the presence of surface CD4 receptor and the chemokine receptor 5 (CCR5) co-receptor. Studies have demonstrated that patients who are homozygous for a 32-bp deletion in the CCR5 allele do not express CD4+ T-cell CCR5 and thus are resistant to HIV-1 infection with HIV-1 strains that use this co-receptor. Stem cells from a homozygous CCR5 delta32 donor were transplanted to an HIV-1-infected individual following standard conditioning for such transplants and resulted in long-term control of the virus without antiretrovirals. Thus, a number of recent insights into immune system function have spawned a new field of interventional immunotherapy and have enhanced the prospect for development of more specific and nontoxic therapies for immune and inflammatory diseases.

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مواضيع ذات صلة

Immune Tolerance and Autoimmunity

Cellular interactions in regulation of normal immune responses

Markers of Granulocytic Maturation

The Complement System Also Protects Against Infection

Monocytopoiesis

Eosinophil Production

Transcription Factors Regulating Myeloid Differentiation and Myeloid-Specific Gene Expression

Cytokine Regulation of Myeloid Proliferation and Differentiation

Neutrophil Granules and Their Content Proteins

Stages of Neutrophil Differentiation

T Lymphocytes, Transfer of Safety Genes, and Strategies to Improve Tumor Cell Specificity

Optimizing T-Cell Trafficking and Overcoming Tumor Immune Evasion