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Although animals can be prophylactically immunized against the growth of tumor implants, most of the attempts to use immunotherapy to cause the regression of animal and human tumors once they become established have been unsuccessful. To understand the nature of this refractoriness we have studied a methylcholanthrene-induced and strongly immunogenic murine fibrosarcoma. In our model, the onset of this refractoriness was associated with the beginning of an immunosuppressive state known as "immunological eclipse" characterized by a loss of the antitumor immune response when tumor grows beyond a critical size. This immunological eclipse was accompanied by the emergence of a systemic inflammatory condition. Treatment of tumor-bearing mice with a single dose of a synthetic corticosteroid, dexamethasone (DX), reduced significantly all parameters of systemic inflammation and simultaneously reversed the immunological eclipse. The reversion of the eclipse upon DX treatment was not curative itself, but allowed an immunological therapy based in dendritic cells pulsed with tumor antigens, which was itself absolutely ineffective, to exert a significant inhibitory effect against an established growing tumor. The two-step schedule using an anti-inflammatory treatment to reverse the immunological eclipse plus a dendritic cell-based vaccination strategy aimed to stimulate the antitumor immune response, could serve eventually as a model of immunotherapy against animal and human tumors.

Regulation of inflammation is a crucial event since its alteration, such as in sepsis and chronic autoimmune (i.e. rheumatoid arthritis, lupus erythematosus) or infectious diseases (i.e. tuberculosis, leprosy), determines severe tissue damage. Although there is a general consensus that regulation of inflammation results from a balance between proinflammatory and antiinflammatory pathways, we arrived at the conclusion that well known chemoattractants/proinflammatory molecules such as bacterial formyl peptides or immune complexes (IC), could induce, paradoxically, strong antiinflammatory effects. Thus, we demonstrated that N-formyl-methionyl-leucyl-phenylalanine (FMLP) exerted a drastic antiinflammatory effect, inhibiting the secretion of tumor necrosis alpha (TNF-alpha) induced by lipopolysaccharides, a potent TNF-alpha inducer. We also determined that in human neutrophils FMLP and IC induced the downregulation of receptors for the Fc portion of IgG (FcgammaRII and FcgammaRIIIB). Moreover, FMLP inhibited interferon gamma (IFN-gamma)-induced FcgammaRI expression and IC downregulate class II molecules of the major histocompatibility complex on monocytes. Part of these effects were mediated by the release of aspartic-, serin-, or metalloproteases. All these results favor the postulation of a new concept on the regulation of inflammation carried out through an alternative and non conventional pathway, in which a chemoattractant/proinflammatory agent could, under certain circumstances, act as an antiinflammatory molecule.

Natural killer (NK) activity is impaired in patients with positive serology for the human immunodeficiency virus (HIV). We previously found an inhibitory effect of sera from hemophilic (He) HIV+ patients on normal NK activity. In the present study, we have further characterized this effect by studying its reversibility, temperature and time incubation dependence. Since interleukin 2 (IL-2) is able to enhance NK levels, we analyzed the capacity of this lymphokine to reverse the effect of He HIV+ sera. We found that when IL-2 activation of NK activity occurred simultaneously or after HIV+ serum-treatment, a significant restoration of NK function was observed. In contrast, preincubation with IL-2 did not affect the inhibitory effect exerted by HIV+ sera.

Bacterial lipopolysacharride (LPS) is the major membrane component of Gram negative bacteria. It is a potent pleiotropic stimulus for the immune system frequently associated with septic syndrome or septic shock. The detoxification of LPS in Gram negative sepsis is one of the important problems to resolve in clinical treatments. In this study we compare the capacity of polymorphonuclear neutrophils (PMN) in LPS detoxification in two different situations: a) when LPS is offered to PMN as an isolated molecule; b) when the LPS offered is part of the whole Gram negative bacteria (E. coli 0111:B4). Our results show that PMN are able to inhibit the capacity of LPS to produce TNF-alpha. However, when whole bacteria, instead of LPS, are incubated with PMN, an enhancement in the production of tumor necrosis factor alpha (TNF-alpha) is observed. The bacterial overburden of PMN is not the reason for the spread of LPS after PMN incubation. Our conclusion is that PMN have a dual capacity to deal with LPS, either inactivating or releasing it depending on how it is offered.