Immunotherapy for autoimmune disease maily include antigen non-specific treatment and antigen specific treatment.
• Targeting T-cell populations and antigen-presenting cells:
Encouraging results have been reported from both animal models and early clinical studies using a mutated, less activating form of anti-CD3 antibody. The use of this antibody avoids the acute cytokine release — that causes a range of problems from malaise to hypotensive shock— induced by non-mutated anti-CD3 antibody.
Therapy using a cytotoxic T-lymphocyte antigen 4 (CTLA4)–immunoglobulin fusion protein, which blocks interactions with CD28, is effective in randomized, double-blind clinical trials in patients with psoriasis and rheumatoid arthritis.
• Targeting cytokines:
About a million patients have been treated with anti-TNF biologicals ( anti-TNF monoclonal antibodies (infliximab29 and adalumimab) and the TNF-receptor (TNFR) fusion protein (etanercept; Enbrel)) so far, and some for over seven years.
Success has also come from IL-1 blockade using the IL-1-receptor antagonist anakinra, which is approved for the treatment of rheumatoid arthritis. And promising results have been seen in the treatment of rheumatoid arthritis with anti-IL-15 antibody. High mobility group 1 (HMGB1), a stimulator of inflammatory responses, is another promising target for arthritis and sepsis. Finally, blocking the receptor activator of nuclear factor NF-kappaB ligand (RANKL), the main activator of osteoclasts, is a promising approach for reducing bone destruction, such as that seen in rheumatoid arthritis.
Initial studies in animal models of multiple sclerosis (EAE) indicated that the critical homing molecule to the inflamed central nervous system (CNS) is alpha4beta1 integrin: anti-alpha4beta1 antibody blocked the entry of lymphocytes into the brain and abrogated the clinical paralysis associated with EAE. This approach also proved successful in patients with multiple sclerosis: a phase III trial of a humanized alpha4beta1-specific monoclonal antibody natalizumab (Tysabri) reduced clinical relapses by 66% over the next year, leading to Food and Drug Administration (FDA) approval of the drug. Encouraging results were seen with the same antibody in the treatment of inflammatory bowel disease.
The administration of glatiramer acetate ameliorated EAE, and is now an approved drug for multiple sclerosis.
An altered peptide ligand (APL) of MBP-derived peptide was constructed by mutating the amino acids that form the main contact sites with the TCR on disease-causing T cells. The administration of the MBP APL ameliorated EAE in mice induced by a different myelin protein (proteolipid protein), even when the APL was administered after the initial attack of paralysis.
A big success has been achieved in immunotherapy drugs for autoimmune disease, especially for antigen non-specific treatment. More progress will be made in the future.
Feldmann M, Steinman L. Design of effective immunotherapy for human autoimmunity[J]. Nature, 2005, 435(7042): 612-619.