CYTOKINES AND THE IMMUNE-RESPONSE

Cytokines participate in many physiological processes including the re gulation of immune and inflammatory responses. These effector molecule s are produced transiently and locally controlling the amplitude and d uration of the response. A variety of experiments has shown that exces sive or insufficient production may significantly contribute to the pa thophysiology of a range of diseases. Particularly cytokines released by CD4(+) T cells at the onset of an immune response are thought to be decisive for pathological or physiological consequences. The meeting in Budapest was focussed on cytokines known to contribute to the patho physiology of autoimmune diseases, infectious diseases and allograft r ejection (e.g., IL-1, IL-4, IL-6, IL-10, IL-12, TNF-alpha and IFN-alph a, -beta, -gamma). A central role for IFN-gamma in autoimmunity was su ggested by blocking experiments in vivo using monoclonal antibodies an d soluble forms of the IFN-gamma receptor (IFN-gamma sR). These agents ameliorated disease development in a variety of experimental autoimmu ne diseases in rodents. In a mouse model for the human disease Myasthe nia gravis, IFN-alpha was found to reduce both the incidence and progr ession of the disease. Treatment of R. aurantiacus-infected mice with anti-IL-4, monoclonal antibodies (mAbs) was reported to interfere with the regression of granulomas in spleen and liver, most likely through inadequate IL-4-mediated suppression of IFN-gamma production. In addi tion, it was shown that mice with disrupted IFN-gamma R genes died rap idly after infection with the BCG strain of M. bovis, whereas normal m ice survived the infection. IL-12 was found to be the main inductor of IFN-gamma during the lethal Shwartzman reaction. TNF-alpha was identi fied as the principal cause of mortality after the second injection wi th LPS. In a variety of studies examining the role of cytokines in the pathogenesis of AIDS, much attention was given to the in vitro effect s of HIV-1 and/or the HIV-1 viral membrane protein gp120 on triggering cytokine production by peripheral blood leukocytes (PBLs) and purifie d monocytes/macrophages (M phi) originating from healthy donors. Gp120 as a sole agent significantly suppressed IFN-gamma production by mito gen-stimulated PBLs and induced the production of IFN-alpha in culture s of normal human peripheral blood mononuclear cells (PBMCs). In a hum an macrophage cell line, TNF-alpha exerted a stimulatory effect on vir al replication and programmed cell death induced by HIV-1 which was po tentiated by the simultaneous incubation with IFN-gamma. Upon transfec tion of human PBLs and CD4(+) T cells with a retroviral vector encodin g human IFN-beta, a notable reduction in reverse transcriptase activit y after HIV-1 challenge was observed. Gp120 was also found to induce b oth IL-6 and TNF-alpha expression and to induce morphological changes reminiscent for apoptosis in primary astrocytes and in a re-aggregated human brain cell model, suggesting a role for these cytokines in the neuropathology of AIDS dementia. Moreover, data were presented indicat ing that cytokine-induced expression of cell adhesion molecules (e.g., ICAM-1) in HIV-1 infected U 937 cells leads to high level incorporati on of this molecule in the membrane of the viral progeny which may pla y a role in the attachment of such virions to CD4-negative cells.