Autoimmunity and the immunotherapy of cancer: targeting the "self" to destroy the "other"

It is increasingly clear that immunity to "self"-antigens may result in tumor destruction in mouse and man. But which antigens should be targeted with therapeutic cancer vaccines? In the case of melanoma, recognition of melanocyte differentiation antigens (MDA) can be associated with autoimmune depigmentation (vitiligo). We propose that intersection of protein transport to melanosomes and endosomes allows for the loading of MDA-derived peptides on MHC class II molecules, resulting in the activation of MDA-specific CD4+ "helper" T cells that aid the induction of melanoma-specific CD8+ T cells. Thus, the immunogenicity of MDA may be a consequence of their unique cell biology. Studies of MDA-based vaccines can provide new insight into the development of more effective cancer vaccines.     

Antigenic heterogeneity of human mononuclear phagocytes: immunohistologic analysis using monoclonal antibodies

Eight monoclonal antibodies to cell surface antigens of human monocytes were evaluated as immunologic markers for recognition of macrophages in sections of normal and diseased tissues, using immunoperoxidase and enzyme histochemical techniques. Monoclonal antibodies assessed were PHM2, PHM3, FMC17, FMC32, FMC33, FMC34, OKM1, and 63D3. Sites studied were human bone marrow, blood, lymph node, spleen, thymus, liver, kidney, lung, and peritoneal lavages, rejecting renal allografts containing inflammatory macrophages, and granulomata showing epithelioid and multinucleate giant cell formation. All antibodies bound to at least some tissue macrophages and, except for FMC32 and FMC33 antibodies, which were identically distributed, each antibody had a distinctive tissue distribution. Some antigens were shared by other bone-marrow-derived cells (megakaryocytes and cortical thymocytes), endothelium, epithelium, and dendritic cells. Antigenic differences were also detected between mononuclear phagocytes present at different sites, different stages of differentiation, and likely different states of activation. These studies provide evidence of major antigenic differences between various populations of human mononuclear phagocytes. They therefore indicate the need for careful evaluation of experiments involving the recognition of macrophages in tissue sections and smears based solely on the use of antimonocyte monoclonal antibodies.     

盐酸塞利洛尔合成工艺改进

目的:合成盐酸塞利洛尔,并进行工艺改进。方法:革除溴化反应,对醚化反应进行了优化。结果:使合成路线缩短一步,醚化收率比文献值提高20％以上。结论:该路线较适合于工业化生产。     

Visualizing fewer than 10 mouse T cells with an enhanced firefly luciferase in immunocompetent mouse models of cancer

Antigen specific T cell migration to sites of infection or cancer is critical for an effective immune response. In mouse models of cancer, the number of lymphocytes reaching the tumor is typically only a few hundred, yet technology capable of imaging these cells using bioluminescence has yet to be achieved. A combination of codon optimization, removal of cryptic splice sites and retroviral modification was used to engineer an enhanced firefly luciferase (ffLuc) vector. Compared with ffLuc, T cells expressing our construct generated >100 times more light, permitting detection of as few as three cells implanted s.c. while maintaining long term coexpression of a reporter gene (Thy1.1). Expression of enhanced ffLuc in mouse T cells permitted the tracking of <3 × 10⁴ adoptively transferred T cells infiltrating sites of vaccination and preestablished tumors. Penetration of light through deep tissues, including the liver and spleen, was also observed. Finally, we were able to enumerate infiltrating mouse lymphocytes constituting <0.3% of total tumor cellularity, representing a significant improvement over standard methods of quantitation including flow cytometry.     

Improving antitumor immune responses by circumventing immunoregulatory cells and mechanisms.

Although numerous immunotherapeutic strategies have been studied in patients with cancer, consistent induction of clinical responses remains a formidable challenge. Cancer vaccines are often successful at generating elevated numbers of tumor-specific T lymphocytes in peripheral blood, however, despite this, tumors usually continue to grow unabated. Recent evidence suggests that endogenous regulatory cells, known to play a major role in the induction of immune tolerance to self and prevention of autoimmunity, as well as suppressive myeloid cells invoked in the tumor-bearing state, may be largely responsible for preventing effective antitumor immune responses. This review will focus on the major regulatory cell subtypes, including CD4(+)CD25(+) T-regulatory cells, type 1 regulatory T cells, natural killer T cells, and immature myeloid cells. Studies in humans and in animal models have shown a role for all of these cells in tumor progression, although the mechanisms by which they act to suppress immunity remain largely undefined. Elucidation of the dominant molecular mechanisms mediating immune suppression in vivo will allow more precise targeting of the relevant regulatory cell populations, as well as the development of novel strategies and clinical reagents that will directly block molecules that induce the suppression of antitumor immunity.