From: Billi Goldberg <bigoldberg@igc.apc.org>
Subject: More on Infections and Th1/Th2
Note: Copyright 1992, Dan R. Greening. Non-commercial reproduction allowed.
Archive-Number: 6450
Organization: unspecified
Date: Thu, 12 Nov 92 10:47:44 PST

Both of these articles by Sher et al. are extremely important and should 
be read in their entirety. It applies theory to the actual control of 
parasitic and retroviral infections in AIDS and involvement of Th1/Th2 
subsets. 

What is really significant is that Alan Sher, PhD, is located at the 
Immunology and Cell Biology Section, Laboratory of Parasitic Diseases, 
National Institue of Allergy and Infectious Diseases, Building 4, Room 
126, NIH, Bathesda, MD 20892, U.S.A.
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Sher A; Gazzinelli RT; Oswald IP; Clerici M; Kullberg M; Pearce EJ;
Berzofsky JA; Mosmann TR; James SL; Morse HC 3d.                       

Role of T-cell derived cytokines in the downregulation of immune 
responses in parasitic and retroviral infection.     

Immunological Reviews, 1992 Jun, 127:183-204.
                                                                               
Abstract: Parasitic infection is frequently accompanied by a 
downregulation in host cell-mediated immunity. Recent studies suggest 
that this modulation of helper T cells and effector cell function can at 
least in part be attributed to the action of a set of inhibitory 
cytokines produced by T lymphocytes as well as by a number of other cell 
types. The best characterized of these inhibitory lymphokines are IL-4, 
IL-10 and TGF-beta. Interestingly, both IL-4 and IL-10 are produced by 
the Th2 but not the Th1 subset of CD4+ helper cells. The former subset 
dominates in many situations of chronic or exacerbated parasitic 
infection and is thought to suppress Th1 function as a consequence of 
the cross-regulatory activity of these two cytokines. The latter 
hypothesis is supported by recent experiments demonstrating that 
mAb-mediated neutralization of IL-10 reverses suppressed IFN-gamma 
responses and/or disease susceptibility in mice with parasitic 
infections. In vivo neutralization of TGF-beta has also been reported to 
increase host resistance to parasite challenge. In addition to 
suppressing T-cell differentiation, function or proliferation, IL-4, 
IL-10 and TGF-beta each inhibit the ability of IFN-gamma to activate 
macrophages for killing of both intracellular and extracellular 
parasites. Moreover, the three cytokines are able to synergize with each 
other in downregulating these parasiticidal effects. Interestingly, each 
of the cytokines inhibits the production of reactive nitrogen oxides, an 
effector mechanism previously demonstrated to play a major role in 
parasite killing by activated macrophages. In the case of IL-10, this 
suppression of nitrogen oxide production appears to result from an 
inhibition of TNF-alpha synthesis leading to defective macrophage 
stimulation. While distant from parasites in their biology and 
phylogeny, some retroviruses also appear to induce an over-production in 
downregulatory cytokines which is closely associated with the onset of 
immunodeficiency. Thus, in an animal model involving infection of mice 
with LP-BM5 MuLV and in human HIV infection, Th2 (IL-10 and/or IL-4) 
cytokine synthesis is increased while Th1 (IFN-gamma and/or IL-2) 
cytokine production is suppressed. These observations suggest that 
cytokine-mediated cross-regulation may play a role in the pathogenesis 
of acquired immune deficiency disease, contributing both to the 
progression of retroviral infection and the increase in susceptibility 
to opportunistic infections and malignancy. Observations of similar 
cytokine cross-regulatory activities in organisms as diverse as 
helminths, protozoa and retroviruses predict that comparable mechanisms 
may operate in a wide variety of infectious diseases.
************************************************************************
Sher A; Coffman RL.

Regulation of immunity to parasites by T cells and T cell-derived
cytokines.

Annual Review of Immunology, 1992, 10:385-409.

Abstract: Parasitic protozoa and helminths are a diverse group of 
organisms which together form a major cause of infectious disease in 
humans and livestock. Studies in animal models have revealed that T 
lymphocytes and the cytokines they produce play a crucial role in 
determining the outcome of parasitic infection in terms of both 
protective immunity and immunopathology. Of particular interest is 
recent evidence that different parasitic infections in the context of 
different host genetic background can trigger polarized CD4+ T cell 
subset responses. The set of cytokines produced by these different T 
helper responses, in turn, can have opposing effects on the parasite, 
resulting in either control of infection or promotion of disease. 
Moreover, cytokines produced by one CD4+ subset can block either the 
production and/or activity of the cytokines produced by the other 
subset. The establishment of this state of cross-regulation may be 
important for parasite survival. CD8+ T cells also appear to play a 
dual effector/regulatory role in parasite immunity and immunopathology, 
although the mechanisms underlying their induction and function are less 
well understood. CD(8+)-mediated cytolytic killing functions have now 
been demonstrated against a number of different intracellular protozoa, 
although IFN-gamma produced by the same effector cells may also be 
critical in host community. In addition to providing highly relevant 
models for studying the selection and immunobiologic function of T-cell 
subsets, research on T lymphocyte-parasite interactions is crucial for 
the design of effective vaccines and immunotherapies and thus has broad 
practical as well as theoretical ramifications.

Newsgroups: sci.med.aids