Signalingand Functional Defects in the Immune Cells of Aged Subjects

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Several studies have shown immunosuppression and alterations in T cell signaling in cancer patients, and more recently in other diseases like chronic infections and autoimmunity. Similiar findings have also been observed in the aging population. We believe a common underlying mechanism(s) may be involved in all of these immunosuppressive conditions. A greater understanding of the biological and molecular mechanism(s) involved in these alterations may aid in the development of a corrective manipulation of the host immune system to overcome or revert these immunological defects. Studies within long term cancer patients as well as patients suffering from chronic inflammation (i.e. Lepromatous Leprosy) have demonstrated various defects in the signaling pathways in human T cells post TCR ligation. More specifically, differences in the TCR zeta chain as well as NFkB expression in T cells derived from these various patients have been observed. Our hypothesis is that aging is a chronic disease and possibly a form of chronic inflammation in that similar immunological alteration may occur in elderly individuals to those that are observed in cancer, AIDS, and leprosy patients. In addition, similar to cancer patients, T cells derived from elderly subjects also exhibit diminished T cell proliferative responses as well as poor T cell calcium and inositol responses post TCR ligation. Tumor cells or regulatory immune cells involved in these inefficient immune processes may also be responsible for releasing soluble factor(s) which may results in these suppressive effects. Additional studies have revealed that a systemic T cell phenotypic switching occurs within AIDS and cancer patients. It has been proposed that, during the aging process, Th1-like cells convert to Th2- or Th3- like cells which are believe to be the more suppressive lymphocyte populations. Defining the various signaling defects and T cell switching within an aged host should permit the generation of models to possibly intervene and alter such changes. A major area of focus this year and in the next year will be the NFkB/IkB and T cell receptor signaling circuits in young and old human T cells as well as in lymphocytes derived from long- term cancer patients. Furthermore, additional signaling molecules and pathways such as JAK, STAT, and various costimulatory and apoptotic molecules will also be examined. Finally, additional studies will be performed examining the effects of various cytokines and hormones at inducing various TCR signaling alterations using primary T cells and/or T cell clones. Various fluids derived from cancer patients as well as culture supernatants derived from activated Th1 and Th2 clones will also be examined for their ability to facilitate signaling alterations. As for the cancer studies, emphasis will be put in tumor types more relevant to the aging population like colon, ovarian, prostate, breast cancers, multiple myeloma, CLL and B- cell lymphomas. Overall, new strategies are needed to improve the ability of the immune system to eradicate the minimal residual disease (therefore treatment failure) after standard chemotherapy. This is especially relevant to older patients whom may have different degrees of immunosuppression and/or less tolerance to some toxic regimens. These studies will hopefully reveal the precise molecular pathways that are defective in cancer patients and elderly subjects. With such an understanding, we may be able to reverse these immune alterations and improve the current anti-tumor strategies.