NetNews Usenet Archive 1992 #26/NN_1992_26.iso/spool/sci/med/aids/2004

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From: Billi Goldberg <[e-mail]>
Subject: More on Infections and Th1/Th2
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Note: Copyright 1992, Dan R. Greening. Non-commercial reproduction allowed.
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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.