Tumor-induced immune dysfunction.

Immune system-based approaches for the treatment of malignant disease over the past decades have often focused on cytolytic effector cells such as cytotoxic T lymphocytes (CTL), and natural killer (NK) cells. It has also been demonstrated that tumor-bearing mice can be cured using a wide variety of approaches, some of which involve cytokine-mediated enhancement of CTL and NK cell activity. However, the apparent success in mice stands in contrast to the current situation in the clinic, wherein only a minority of patients have thus far benefited from CTL- or NK cell-based antitumor approaches. The underlying causes of tumor-associated immune suppression of CTL and NK cell activity are discussed, and features of interest shared with HIV infection, leprosy, and rheumatoid arthritis are also be mentioned. Remarkable and very recent observations have shed more light upon the causes of dysfunctional alterations in CTL and NK cells often associated with these diseases, that in turn have suggested new immunotherapeutic approaches for cancer and infectious disease.

[Immunology of leprosy. Review of data from the 1980-1990 time period]. / Immunologie der Lepra. Ubersicht zu Daten des Zeitraumes 1980-1990.

The classification used for leprosy so far distinguishes between two polar forms (pauci-bacillary and multi-bacillary), with different influences on the immune cells. The identification of specific antigens of the germ surface with monoclonal antibodies allows finer differentiation in classification, which now extends to transitional forms of clinical relevance. The current status of knowledge about immunological phenomena triggered by Mycobacterium leprae is complex, and controversy is rife at present. The bacillus is comparable to other mycobacteria in antigenicity. Owing to the complicated composition of the cellular envelope, few epitopes are accessible for immunological reactions. Investigation on the behaviour of T-lymphocytes in combination with analysis of the bacterial surface structures led to the development of a new pathogenetic concept. In spite of different immunological and inflammatory reactions in patients (reflecting the individual pathology), the discrimination between a partial and a total immunological defect is made. So far, no histocompatibility-antigen type has been found that allows recognition of the predisposition to infection. Immunity against the bacteria is achieved after BCG in some cases. All this suggests that the development of a vaccine via biotechnical synthesis of idiotypes and anti-idiotypes may be possible.

Mechanisms of immunosuppression.

Immunosuppresive disease is a major economic concern in domestic poultry production. Although many immunosuppressive agents have been described, mechanisms of how infectious and noninfectious agents compromise the immune system are poorly understood in avian species. Two categories, generalized and antigen-specific immunosuppression have been described in mammals. Generalized immunosuppression produces overall reduced responsiveness and increased susceptibility to a wide variety of infectious and neoplastic diseases. The best characterized immunosuppressive mechanisms are described in HIV-1 infections that lead to acquired immune deficiency syndrome (AIDS) in humans. In contrast, the antigen-specific suppression observed in human leprosy illustrates how an infecting agent selectively suppresses host responses against itself favoring bacterial spread. Both diseases have well-defined clinical staging classifications that correlate with specific immunological defects. An approach to studying immunosuppressive mechanisms in the avian suggests the need for relating pathogenesis with tests of immune responsiveness using a series of increasingly more specific immunological assays to pinpoint defects.

HLA-DQ molecules and the control of Mycobacterium leprae-specific T cell nonresponsiveness in lepromatous leprosy patients.

The major histocompatibility complex (MHC) controls of the outcome of the immune response to T cell-dependent antigens by dictating whether T cell responsiveness will result (MHC-immune response [Ir]genes) or alternatively T cell nonresponsiveness will occur, possibly through the activation of suppressor cells (MHC-immune suppression [Is] genes). In mice, I-A molecules typically restrict antigen-specific helper T cells. In contrast, H-2 I-E molecules have been reported to control nonresponsiveness to a variety of antigens through antigen-specific suppressor cells. In analogy, HLA-DR molecules are the dominant restriction elements for helper T cells in man. This forces the question whether DQ molecules may be involved in controlling nonresponsiveness in man, e.g. through suppression. In one system, T cell nonresponsiveness to Schistosoma japonicum, evidence has been presented supporting this notion. We have now used a second system, Mycobacterium leprae-specific T cell nonresponsiveness, that is typically found in lepromatous leprosy patients. We find positive but limited evidence for a role for HLA-DQ molecules in controlling T cell nonresponsiveness to M. leprae of the 22 nonresponder patients tested, 4 showed a proliferative T cell response to M. leprae after the addition of DQ- but not DR-specific mAb to the cell cultures. In one of the four BCG nonresponders, anti-DQ mAb had a similar effect.