Preparations and methods for the treatment of T cell mediated diseases

#The present invention relates to compositions and methods of reducing the severity of insulin-dependent diabetes mellitus or insulitis. The invention further relates to compositions and methods of reducing or inhibiting β-cell destruction. The invention further relates to compositions and methods of reducing the severity of latent diabetes. More generally, the invention relates to vaccine therapy for T-cell mediated diseases, and in particular to therapeutic preparations comprising peptides recognized by T cells involved in the pathogenesis of T cell mediated diseases, such as autoimmune diseases, and a metabolizable lipid emulsion as a biologically active carrier.

#Autoimmune disorders, e.g., insulin-dependent diabetes mellitus (IDDM or type I diabetes), multiple sclerosis, rheumatoid arthritis and thyroiditis, are characterized by reactivity of the immune system to an endogenous antigen, with consequent injury to tissues. These immune responses to self-antigens are maintained by the persistent activation of self-reactive T lymphocytes.

#T cells of the CD4 “helper” type have been divided into two groups by the characteristic cytokines they secrete when activated (Mosmann and Coffman, 1989). THI cells secrete IL-2, which induces T cell proliferation, and cytokines such as IFN-γ, which mediate tissue inflammation. TH2 cells, in contrast, secrete IL-4 and IL-10. IL-4 helps T cells secrete antibodies of certain IgG isotypes and suppresses the production of THI inflammatory cytokines (Banchereau et al., 1994). IL-10 indirectly inhibits THI activation by affecting antigen-presentation and inflammatory cytokine production by macrophages (Moore et al., 1993). It is the THI cells which contribute to the pathogenesis of organ-specific autoimmune diseases. TH1-type responses also appear to be involved in other T cell mediated diseases or conditions, such as contact dermatitis (Romagnani, 1994).

#FIG. 1 shows anti-p277 antibody production in NOD mice treated with the peptide p277(Val6-Val11) in: (i) INTRALIPID® or (ii) phosphate-buffered saline (PBS), as described in Example 2.

#FIG. 2 shows TH2-dependent antibody isotypes induced in NOD mice by treatment with the peptide p277(Val6-Val11) in INTRALIPID®, as described in Example 3 below.

#FIGS. 3A-B show that p277(Val6-Val11)/INTRALIPID® therapy induces in NOD mice a specific switch in the profile of cytokines produced by the T-cells reactive to the p277(Val6-Val11) peptide, as described in Example 4. FIG. 3A shows that there is a reduction of TH1 (IL-2, IFN-γ) and elevation of TH2 (IL-4, IL-10) cytokines after treatment of the mice with the p277(Val6-Val11) peptide in INTRALIPID® and incubation of the spleen cells with p277(Val6-Val11); FIG. 3B shows that there is no change in the cytokines after treatment of the mice with the p277(Val6-Val11) peptide in INTRALIPID® and incubation of the spleen cells with Con A.

#The present invention relates to compositions and methods of reducing the incidence or severity of insulin dependent diabetes mellitus (IDDM) or insulitis and further relates to compositions and methods of reducing or inhibiting β-cell destruction. The present invention further relates to compositions and methods of reducing the severity of latent autoimmune diabetes in adults (LADA).

#The present invention relates to compositions used for the treatment of IDDM or insulitis or β-cell destruction or LADA, comprising a peptide or other antigen and a biologically active lipid carrier, wherein the peptide or other antigen is recognized by inflammatory T-cells associated with the pathogenesis of said disease or condition, and the biologically active lipid carrier is a fat emulsion comprising about 5-25% triglycerides of plant and/or animal origin, about 0.1-3% phospholipids of plant and/or animal origin, about 1.5-4.5% osmo-regulator, and optionally about 0-0.5% antioxidant, and sterile water to complete to 100%.

#The present invention also provides methods of reducing the severity of IDDM or insulitis or β-cell destruction or LADA comprising administering to a patient having said disease a pharmaceutical composition of an antigen or a peptide and a carrier, wherein the antigen is recognized by inflammatory T cells associated with the pathogenesis of said disease and the carrier is a metabolizable lipid emulsion, said composition induces a TH1→TH2 shift in the cytokines produced by said T cells. Typically the composition is administered in an amount sufficient to reduce the severity of symptoms associated with said disease or to halt or slow the progression of the disease.