mart-1-antigen and Autoimmune-Diseases

The genetic introduction of T cell receptor genes into T cells has been developed over the past decade as a strategy to induce defined antigen-specific T cell immunity. With the potential value of TCR gene therapy well-established in murine models and the feasibility of infusion of TCR-modified autologous T cells shown in a first phase I trial, the next key step will be to transform TCR gene transfer from an experimental technique into a robust clinical strategy. In this review, we discuss the different properties of the TCR transgene and transgene cassette that can strongly affect both the efficacy and the safety of TCR gene transfer.

Topics: Animals; Antigens, Neoplasm; Autoimmune Diseases; Clinical Trials, Phase I as Topic; Codon; Dimerization; Feasibility Studies; Genes, Synthetic; Genes, Transgenic, Suicide; Genetic Therapy; Genetic Vectors; Humans; Immunotherapy, Adoptive; MART-1 Antigen; Melanoma; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Proteins; Neoplasms, Experimental; Receptors, Antigen, T-Cell; Species Specificity; T-Lymphocyte Subsets; Transgenes

Vogt-Koyanagi-Harada (VKH) disease is a systemic disorder affecting systemic melanocytes including those in the eyes, meninges, ears, skin, and hair. Although the pathogenic mechanisms of the disease are still controversial, there is clinical and experimental evidence that the disease is an autoimmune disease involving melanocytes. In this study, we investigated whether patients with VKH disease have immune responses specific to melanocyte antigens, and whether T lymphocytes of these patients cross-react with peptides of melanocytes and with exogenous antigens. Cells infiltrating the eyes in HLA-DR 4+ patients with VKH contained a population of CD 4+ T lymphocytes that recognized tyrosinase and gp 100 peptides and produced cytokines in response to these two peptides. The CD 8+ T cells recognized the MART-1 melanocyte peptide, but not the CD 4+ T cells. When a search was made for molecular mimicry between melanocyte antigens and exogenous antigens by database screening, cytomegalovirus envelope glycoprotein H (CMV-egH) had high amino acid homology with the tyrosinase peptide. Some of the T cells taken from VKH patients recognized melanocyte peptides including the tyrosinase peptide as well as the CMV-egH290-302 peptide, which had a high amino acid homology to the tyrosinase peptide. CMV peptide-specific T cells showed significant proliferation in response not only to CMV-egH290-302, but also to tyrosinase450-462. The seroprevalence of CMV was significantly higher in VKH patients. In addition, all tested samples of VKH patients were negative for CMV-DNA. These results indicate that CMV infection may stimulate the production of T cells that crossreact with tyrosinase by molecular mimicry. These events may be responsible for the onset of VKH disease.

Topics: Antigens, Neoplasm; Autoimmune Diseases; CD4-Positive T-Lymphocytes; Humans; MART-1 Antigen; Melanocytes; Neoplasm Proteins; Uveomeningoencephalitic Syndrome

Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) blockade with CP-675,206, a fully human anti-CTLA4 monoclonal antibody, may break peripheral immunologic tolerance leading to effective immune responses to cancer in humans. A phase I trial was conducted to test the safety of CP-675,206.. Thirty-nine patients with solid malignancies (melanoma, n = 34; renal cell, n = 4; colon, n = 1) received an intravenous (IV) infusion of CP-675,206 at seven dose levels. The primary objective was to determine the maximum-tolerated dose and the recommended phase II dose.. Dose-limiting toxicities and autoimmune phenomena included diarrhea, dermatitis, vitiligo, panhypopituitarism and hyperthyroidism. Two patients experienced complete responses (maintained for 34+ and 25+ months), and there were two partial responses (26+ and 25+ months) among 29 patients with measurable melanoma. There have been no relapses thus far after objective response to therapy. Four other patients had stable disease at end of study evaluation (16, 7, 7, and 4 months). Additionally, five patients had extended periods without disease progression (36+, 35+, 26+, 24+, and 23+ months) after local treatment of progressive metastases. Longer systemic exposure to CP-675,206 achieved in higher dose cohorts predicted for a higher probability of response.. CP-675,206 can be administered safely to humans as a single IV dose up to 15 mg/kg, resulting in breaking of peripheral immune tolerance to self-tissues and antitumor activity in melanoma.

Topics: Adult; Aged; Antibodies, Blocking; Antibodies, Monoclonal; Antibodies, Neoplasm; Antigens, CD; Antigens, Differentiation; Antigens, Neoplasm; Autoimmune Diseases; Cancer Vaccines; Colonic Neoplasms; CTLA-4 Antigen; Female; Humans; Immune Tolerance; Immunotherapy; Infusions, Intravenous; Kidney Neoplasms; Male; MART-1 Antigen; Melanoma; Middle Aged; Neoplasm Proteins; Neoplasms; Regression Analysis; T-Lymphocyte Subsets; Treatment Outcome