Antitumor Immunity And Autoimmune Disease

It is becoming increasingly accepted that a large set of antigenic determinants of the self have not induced self-tolerance [99], and that a number of these peptide determinants furnish target structures for immune responses directed against tumors. As illustrated by the results of the hunt for tumor-associated antigens in recent years, tumors do not express mysterious nonself- or neoself-antigens, but rather a set of genes that are part of the self/altered self-repertoire. In fact, the aberrant expression of autoantigens by tumor cells and the possibility of inadvertent induction of auto-toxicity as a byproduct of antitumor immunity was evident long before the elucidation of the self-nature of tumor antigens. Paraneoplastic syndromes, a heterogeneous group of immune mediated neuronal degeneration observed in a number of cancer patients with distinct types of tumors, provided some insight into the increasingly blurred boundary between antitumor immunity and autoimmunity [100], Paraneoplastic syndromes are triggered when antigens, normally restricted to the nervous system, are aberrantly expressed in a cancer. The immune system recognizes the antigen expressed by the tumor cells and mounts an immune response. This immune response, which was found to effectuate retardation of the growth of the tumor in some cases, would also attack those portions of the nervous system that express the "onconeural" antigen. The result is that the tumor remains small but patients may suffer severe neurological disorders [101, 102],

Further evidence to the coexistence of antitumor immunity and autoreactivity was brought about through observations by Rosenberg and coworkers that in patients with metastatic melanoma who were treated with high-dose interleukin-(IL)-2 immunotherapy, vitiligo, which is a manifestation of normal melanocyte destruction, developed in 15% of those patients who showed significant tumor regression, whereas none of the patients who did not receive the treatment developed vitiligo [103]. Furthermore, autoimmune-related thyroiditis was also observed to associate with an antitumor response in melanoma patients given IL-2, with the incidence of hypothyroidism positively correlating with a favorable antitumor response. [104], Studies aiming at defining the molecular targets of antimelanoma cytotoxic T lymphocytes showed that those CTLs recognized a series of HLA class-I-restricted antigenic peptides having self-sequences [105]. These findings suggested the existence of a mechanism, shared by antitumor immunity and autoimmune disorders, whereby T cells that recognize normal self-sequences become activated.

Animal models have been developed to address the question of whether antigen-specific immunotherapy can induce antitumor effects without autoimmune toxicity when the target antigen is expressed on both tumor cells and normal tissues. In a transgenic mouse model, T cells specific for the env-encoded protein of the murine erythroleukemia tumor FBL were adoptively transferred into tumor-bearing mice expressing the env transgene in peripheral tissues [106]. Remarkably, the FBL tumor was eradicated by the transferred T cells without toxicity to the env-expressing normal tissues of the transgenic mouse. Another approach that projects more accurately the spontaneous nature of human tumors, Speiser and coworkers [107] developed a double transgenic mouse model that expresses the transforming simian virus 40 tumor T antigen and the mock tumor-associated antigen glycoprotein (GP) of the lymphocytic choriomeningitis virus (LCMV) under the rat insulin promoter. These mice develop spontaneous insulinomas and, as a result, succumb to progressive hypoglycemia. Infection of these mice with the LCMV virus induces a strong CTL response that leads to rejection of the tumors and renders the mice normoglycemic. Surprisingly, however, the double transgenic mice did not develop chronic autoimmune insulinitis although not only the tumor cells but also normal ft cells were targets for CTLs [108], The reason for this apparent tumor selectivity by the CTL response could be attributed to the transient nature of the CTL response, which abated after clearance of the LCMV infection despite the persistence of antigen expression by both the tumor and the B cells of pancreas. The fact that the CTL activity was limited in time precluded the induction of chronic autoimmune disease, in spite of initial induction of insulinitis, while allowed for the successful in vivo rejection of the established tumor.

The PI A antigen of the murine mastocytoma P815 is one of the earliest tumor-associated antigens to be characterized [109], This antigen was subsequently found to be expressed on a number of murine tumors as well as the testis and the placenta, a pattern of expression which is similar to that of the MAGE, BAGE and GAGE family of genes that code for tumor antigens recognized by autologous CTLs. The induction of anti-PlA cytotoxic T lymphocytes did not effectuate any autoimmune side effects in male or female mice, with no deleterious effects on either fertility or gestation, respectively [110], A possible explanation for the normal tissue-sparing CTL response is the lack of expression of MHC class-I molecules on spermatogonia or trophoblasts. Although other unidentified mechanisms might also play a role in the protection of normal tissues.

The overexpressed tumor-selective autoantigens present a special case. Vaccine studies in rats in which the generation of HER-2/neu-specific immunity revealed no evidence of autoimmunity [111]. In the adult, HER-2 neu is expressed at low basal levels in a number of normal tissues, including skin, digestive tract epithelium, breast, ovary, hepatocytes and alveoli [112]. When rats were immunized with rat

HER-2/neu peptide vaccines, resulting in the generation of HER-2/neu immunity, these tissues showed no histological evidence of lymphocyte infiltration or tissue destruction. The tumor suppressor protein p53 is another molecule which is overexpressed in close to 50% of all human malignancies, which makes it an attractive target for immunotherapy. CTLs specific for the wild-type p53 were generated by immunizing p53 gene-deficient mice with syngeneic p53-overexpressing tumor cells. Adoptive transfer of these CTLs into tumor-bearing p53+/+ nude mice resulted in complete and permanent tumor eradication. Importantly, this occurred in the absence of any histologically demonstrable damage to normal tissues [113]. At a glance, it looks as if immunization against antigens such as HER-2/neu or p53 does not lead to autoimmune damage in normal tissues, where the same antigen is expressed at low levels. It has recently been shown that recognition of CTL epitopes require the expression of the encoding gene above a certain threshold [114]. In some cases, this threshold may not be reached in normal tissues. This phenomenon may, at least partially, explain the apparent margin of tumor specificity in immunization experiments employing these molecules as target antigens. The tumor specificity should, however, be considered with some caution. The weak expression of such molecules measured at the RNA level in a given type of normal tissue my in fact reflect expression strong enough to exceed the threshold, but only in a small subtype of cells. The scarcity of cell lines derived from normal tissues precludes the ability to test the in vitro susceptibility to lysis by CTLs raised against these widely expressed molecules.

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