protective effects have been demonstrated in a variety of animal models of autoimmunity, such as EAE (see Section 15-5) and diabetes, as well as in transplantation. The major drawback of vitamin D3 is that its immunomodulatory effects are seen only at dosages that would lead to hypercalcemia and bone resorption in humans. There is a major search under way for structural analogs of vitamin D3 that retain the immunomodulatory effects but do not cause hypercalcemia.
16-12 Controlled administration of antigen can be used to manipulate the nature of an antigen-specific response.
In some diseases, the target antigen of an unwanted immune response can be identified. It can then be possible to use the antigen itself, rather than drugs or antibodies, to treat the disease, because the manner of antigen presentation can alter the immune response and reduce or eliminate its pathogenic features. As discussed in Section 14-13, this principle has been applied with some success to the treatment of allergies caused by an IgE response to very low doses of antigen. Repeated treatment of allergic individuals with increasing doses of allergen seems to divert the allergic response to one dominated by T cells that favor the production of IgG and IgA antibodies from B cells. These antibodies are thought to desensitize the patient by binding the small amounts of allergen normally encountered and preventing it from binding to IgE.
There has been considerable interest in using peptide antigens to suppress pathogenic responses in T-cell-mediated autoimmune disease. The type of CD4 T-cell response induced by a peptide depends on the way in which it is presented to the immune system (see Section 9-18). For instance, peptides given orally tend to induce regulatory T cells through production of transforming growth factor (TGF)-β, but do not induce TH1 cells or systemic antibody production (see Section 12-14). Indeed, experiments in animals indicate that oral antigens can protect against induced autoimmune disease. Diseases resembling multiple sclerosis or rheumatoid arthritis can be induced in mice by the injection of myelin basic protein (MBP) or collagen type II, respectively, in Freund’s complete adjuvant (see Section 16-29). Oral administration of MBP or type II collagen inhibits the development of these diseases in animals, but oral administration of the whole protein in patients with multiple sclerosis or rheumatoid arthritis has had marginal therapeutic effects. Similarly, no protective effect was found in a large study that examined whether giving low-dose parenteral insulin could delay the onset of diabetes in people at high risk of developing the disease.
Other approaches using antigen to shift the autoimmune T-cell response to a less damaging TH2 response have been more effective in humans. The peptide drug glatiramer acetate (Copaxone) is approved for treating multiple sclerosis, in which it may reduce relapse rates by up to 30%. It is a polymer consisting of the four amino acids glutamic acid, alanine, tyrosine, and lysine in ratios that mimic their composition in MBP, and it induces a TH2-type protective response. A more refined strategy uses altered peptide ligands (APLs), in which amino acid substitutions have been made in specific amino acids in an antigenic peptide that are at the T-cell receptor contact positions. APLs can be designed to act as partial agonists or antagonists, or to induce regulatory T cells. But despite the success of APLs in treating EAE in mice, a trial of these peptides for multiple sclerosis in some patients led to exacerbated disease or to allergic reaction associated with a vigorous TH2 response, and their value in humans remains to be seen.
Summary.