History

Encyclopedia of Cancer. Springer-Verlag (2015)


The concept of immunoediting is predicated on the insight that the immune system can recognize tumor cells. The notion that the immune system monitors the host, not only for pathogen invasion but also for neoplastic changes, arose early in the history of immunology and was first proposed by Paul Ehrlich in 1909 and then resurrected 50 years later by Burnet and Thomas. These early immunologists proposed that the immune system recognizes cells that have undergone neoplastic changes and eliminates them before they can form tumors, a concept known as immune surveillance. However, although this notion has been around for nearly a century, it was not until the twenty-first century that it was unequivocally demonstrated in murine models when Schreiber and colleagues, in 2001, examined the incidence of adenomas and carcinomas in aging wild-type mice compared to mice lacking the recombinase-activating gene-2 (RAG2). The RAG2 gene controls the V(D)J recombination of genes required to generate B cell and T cell antigen-specific receptors. In its absence, or the absence of its partner in this process, RAG1, the development of lymphocytes that bear these receptors is aborted. Thus in mice that lack RAG1 or RAG2, T cells, B cells, and NKT cells fail to develop and the mouse has no adaptive immune response. The Schreiber lab showed that these immunodeficient mice had a higher incidence of spontaneous cancer and were more susceptible to carcinogen-induced sarcomas. These tendencies were increased in mice lacking not only the RAG2 gene but in addition the STAT-1 gene, which controls the interferon gamma signal transduction pathway. Thus both adaptive immune effector cells and the multifunctional lymphokine IFN-g were shown to play a clear role in immunosurveillance. However, in the process of studying immunosurveillance, the Schreiber group made the interesting observation that a high proportion of tumors that emerged in carcinogen-treated RAG2-deficient mice failed to grow in wild-type mice indicating that within the population of tumor cells that arose in the immunodeficient mice were cells that could be recognized and eliminated by an intact immune system. In contrast tumors that arose in wildtype mice were less immunogenic and would grow when transplanted into either wild-type or RAG2deficient mice. Schreiber termed this process by which the immunological environment alters the immunogenicity of tumors “immunoediting.”

 

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