Publications by Year: 1996

Androgen-ablative therapy for metastatic prostate cancer is effective for 60%-80% of men, but its effects are always finite and the majority of men develop androgen-independent disease within two years. Although current therapies for androgen-independent disease have not been shown to impact on survival, recent clinical and laboratory insights offer hope for effective therapy. For instance, recent data indicate that androgen-independent disease may still be dependent on hormonal stimulation, suggesting that hormonally based therapies may provide continued benefit. Chemotherapy, especially with estramustine and etoposide, seems to be an effective combination for a majority of patients. Treatment with suramin had been hampered by its side effects, but new dosing schedules are effectively circumventing toxicity. Radioisotopes such as strontium 89 have been shown to provide effective palliation for a majority of androgen-independent patients. Overall, these and other emerging efforts may be the foundation for therapies that offer hope for a significant survival benefit.

The human intestine contains two populations of anatomically distinct T cells, intraepithelial lymphocytes and lamina propria lymphocytes (LPLs), both of which preferentially use the TCR-alpha beta. Recent studies of TCR alpha- and beta-chain usage by intestinal intraepithelial lymphocytes, which are predominantly CD8+ T cells, have demonstrated that these cells are oligoclonal in normal intestine. This report examined the TCR beta-chains expressed by purified CD4+ and CD8+ T cells from normal colonic lamina propria and from the intestinal mucosa of patients with active ulcerative colitis (UC). The selective expansion of CD8+ T cell clones, and to a lesser extent CD4+ T cell clones, was observed among both normal LPLs and mucosal T cells in UC. These expanded LPL clones from normal donors were all distinct, but the mucosal T cells isolated from five of nine patients with UC contained CD8+ T cells expressing related V beta 3-J beta 1.6 TCRs. These observations provide evidence for an Ag-specific mucosal T cell response in UC. Further studies will be required to identify this Ag and address whether the T cell response to it plays a primary role in initiating the disease or is secondary to the inflammatory response.

Several lines of evidence indicate that a subset of murine intestinal intraepithelial lymphocytes (iIEL), particularly those which express the CD8 alpha alpha homodimer, mature extrathymically. This study confirms that a small fraction of adult human iIEL also express the CD8 alpha alpha homodimer and demonstrates that most of these cells in the small intestine are T cells using the alpha beta T-cell receptor (TCR). Whether these cells or other subsets of adult human iIEL mature extrathymically in the intestine was assessed by measuring the expression of terminal deoxynucleotidyltransferase (TdT), an enzyme expressed exclusively by immature lymphocytes. Very low levels of TdT message could be detected by polymerase chain reaction (PCR) amplification in some iIEL samples. The level of TdT expression was assayed by competitive PCR amplification and compared with thymocytes and peripheral blood lymphocytes. These measurements indicated that the number of immature T cells expressing TdT in the intestinal epithelium was less than one cell per 10(7) lymphocytes. This demonstrates that there are few if any TdT expressing immature T cells in the adult human intestinal mucosa and indicates, therefore, that T-cell development in the intestinal mucosa does not contribute significantly to the T-cell repertoire of the adult human intestine.

The exquisite hormonal dependence of prostate cancer continues to provide an opportunity and a challenge for oncologists. It is clear that future efforts in the laboratory should include determining the frequency and spectrum of AR mutations in AI prostate cancer, the development of more effective antiandrogens, and understanding in greater detail how the AR stimulates the growth of prostate cancers. These efforts may eventually lead to treatments that greatly reduce any stimulatory effects of the AR on prostate cells, possibly resulting in a significant improvement in disease-free survival and, perhaps in conjunction with other modalities, cure of some earlier stages of disease. And even for patients with advanced disease, because hormonal therapy is generally fairly well tolerated even in the typically older prostate cancer patient, defining the contribution of AR-mediated growth to AI disease will be critically important.

A population of mature CD4-CD8-double-negative T cells that expresses an invariant Valpha24-JalphaQ TCR has been identified in humans; the majority of these cells appear to express Vbeta11. A closely related in variant TCRalpha chain is also expressed by a population of NK1+ murine T cells, but these cells may be either CD4+ or double negative. In this report, multiple CD4+ or double-negative Valpha24+Vbeta11+ T-cell clones were isolated, and only the double-negative clones were found to express the invariant TCRalpha chain. Studies of TCRbeta chains expressed by these cells demonstrate that a subset in some donors use Vbeta genes other than Vbeta11. Characterization of Vbeta11 TCRs in one donor by CDR3-length analysis was also carried out. The results indicate that multiple Vbeta11 TCRs of differing CDR3 lengths may associate with the invariant TCRalpha chain.