To study the effects of localized secretion of cytokines on tumor progression, the gene for human interleukin 2 (IL-2) was introduced via retroviral vectors into CMS-5 cells, a weakly immunogenic mouse fibrosarcoma cell line of BALB/c origin. Secretion of low levels of IL-2 from the tumor cells abrogated their tumorigenicity and induced a long-lasting protective immune response against a challenge with a tumorigenic dose of parental CMS-5 cells. Co-injection of IL-2-producing CMS-5 cells with unmodified tumor cells inhibited tumor formation even when highly tumorigenic doses of CMS-5 cells were used. Cytolytic activity in mice injected with parental CMS-5 cells was transient and was greatly diminished 3 wk after injection, as commonly observed in tumor-bearing animals. However, in mice injected with IL-2-producing cells, tumor-specific cytolytic activity persisted at high levels for the duration of the observation period (at least 75 d). High levels of tumor-specific cytolytic activity could also be detected in parental CMS-5 tumor-bearing animals 18 d after inoculation with tumor cells, if IL-2-producing CMS-5 cells but not unmodified parental tumor cells were used as targets. These studies highlight the potential advantages of localized secretion of cytokines mediated via gene transfer to induce potent anti-tumor immune responses.

Although it is too early to assess the long-term effects, the research programs offered led to greater numbers of students who did research, including those in traditionally underrepresented groups. Moreover, students were highly satisfied with their experiences, with 80% feeling that it increased their interest in applying principles they learned to the practice of medicine.

We have previously reported that CTL were demonstrable early after inoculation of CMS5 fibrosarcoma cells, but that they disappeared within 3 wk. These mice were unable to reject a challenge with CMS5 tumor cells. Other studies demonstrated cell surface phenotype and signaling abnormalities of cells within the spleen. Since we assumed that such an environment would make it more difficult to elicit antitumor immune responses via immunotherapy, we asked whether resection of the tumor could reverse these abnormalities. Although early after tumor cell inoculation tumor resection leads to the development of immunity, the effect at late time points has not been studied critically. To test this, mice were inoculated s.c. with CMS5 cells and after 28 days the tumors were resected. We observed a gradual normalization of the cellular phenotype of the spleen. In particular, there was a decrease in the number of Mac1+/Gr1high cells and an increase in the number of CD3+ cells in the spleen within 24–48 h of tumor resection. By day 10, these values were normal. Levels of p56lck increased as well. The functional implications of these changes were illustrated by the reduced growth rate or the complete rejection of a challenge of tumor cells in the resected mice. Both CD4+ and CD8+ cells were involved in the restoration of tumor immunity. Our results suggested that tumor resection not only led to the reversal of immune suppression, but also unmasked a population of primed T cells able to mediate protective immunity.

The mixed leukocyte culture (MLC) and the cell mediated lympholysis (CML) assays are used as in vitro models of the afferent, or recognitive, and efferent, or destructive, phases of the homograft reaction. Activity in both of these tests has been related to differences at the major histocompatibility complex, HL-A in man and H-2 in mouse. Recent evidence suggests that the presumed cell surface differences which lead to cell proliferation in MLC are different from those which act as a target for CML. Data are presented providing further support for this hypothesis; in addition separate cell populations may respond to the differences which activate cells in MLC and to the differences which serve as targets for CML. There thus appears to be a dichotomy both for genetic control of, and cell populations involved in, the recognitive and destructive phases of cell mediated immunity.

Clinician-scientists are important members of a research community that has more opportunities than ever before to solve problems important to patients. Nevertheless, the number of physicians applying for and receiving grants from the National Institutes of Health (NIH) has dropped. Introducing medical students to research and relevant support mechanisms early in their education may help to reverse this trend. In 1995, the Mount Sinai School of Medicine created its Office of Student Research Opportunities (OSRO) to stimulate students to engage in research. It also appointed a new dean to direct the OSRO; the person who filled this new position was a senior faculty member involved in patient-oriented research. The OSRO advises students, identifies faculty who want to mentor students, sponsors the Distinction in Research program, organizes an annual research day, helps fund summer and full-time research, and has created an endowment to support student travel to national meetings. Between 1997 and 2000 the number of students who participated in the research day increased from 18 to 74, and the number of publications by the graduating classes increased from 34 to 58 between 1997 and 1999. Participants have presented both basic and clinical projects. The authors' experience has shown that medical students can be motivated to carry out research with appropriate encouragement from the administration and the faculty, something that may help to reverse a troubling national trend. Based upon these early successes, Mount Sinai is developing a novel five-year program to provide medical students with research training.

Synthesis of interleukin-2 (IL-2) by lymphocytes from 26 insulin-dependent diabetic subjects (IDDM) was compared with that by lymphocytes from 24 nondiabetic control subjects. The control group produced 1.001 +/- 0.071 U/ml (mean +/- SEM). The IDDM group, containing patients diagnosed between 5 days and 10 yr before testing, produced only 0.59 +/- 0.050 U/ml (P less than 0.002). IL-2 synthesis by 6 non-insulin-dependent diabetic subjects (NIDDM) was not decreased (mean +/- SEM, 1.20 +/- 0.04 U/ml). Moreover, decreased levels of IL-2 production was found with lymphocytes of patients in good control, as well as those in poor control. These data suggest that decreased IL-2 synthesis is specific for IDDM, not explainable solely as a consequence of poor metabolic control, and thus, might be involved in the pathogenesis of the disease.

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Medical student education continues to evolve, with an increasing emphasis on evidence-based decision making in clinical settings. Many schools are introducing scholarly programs to their curriculum in order to foster the development of critical thinking and analytic skills, encourage self-directed learning, and develop more individualized learning experiences. In addition, participation in rigorous scholarly projects teaches students that clinical care and research should inform each other, with the goal of providing more benefit to patients and society. Physician-scientists, and physicians who have a better appreciation of science, have the potential to be leaders in the field who will deliver outstanding clinical care, contribute new knowledge, and educate their patients.