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Memórias do Instituto Oswaldo Cruz
Fundação Oswaldo Cruz, Fiocruz
ISSN: 1678-8060 EISSN: 1678-8060
Vol. 93, Num. 3, 1998, pp. 403-404
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Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 93 (3), May/June 1998, pp.
403-404
RESEARCH NOTE
Cytokine Profile and Natural Killer Activity among Brazilian
HIV-1-Infected Subjects
AJS Duarte^+, MA Hong, LS Camargo, DF Nunes, A Carvalho, MN Sato, G
Benard, LFM Brigido, J Casseb
Laboratorio de Imunogenetica e Transplante Experimental, Faculdade de
Medicina, Universidade de Sao Paulo, Av. Dr. Arnaldo 455, sala 2345,
01246-903 Sao Paulo, SP, Brasil
^+Corresponding author. Fax +55-11-3064 0879
Received 11 March 1998; Accepted 16 April 1998
Code Number:OC98077
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RESEARCH NOTE
Key words: HIV - cytokines - NK cells - Brazil
The immune system is progressively affected during HIV infection. Several
mechanisms have been described regarding the HIV/AIDS immunopathogenesis,
some related to the humoral response and others to the cellular immune
response. The changes in the pattern of cytokine production by peripheral
blood mononuclear cells (PBMC) have been particularly studied in order to
better understand the immunoregulation during HIV disease progression.
It has been reported by some authors that PBMC production of interleukin
(IL)-2 and interferon gamma (IFN-g), known as T-helper type 1 cytokines,
decreases with progression of HIV infection (M Clerici et al. 1993
Immunol Today 14: 107-111, E Maggi et al. 1994 Science 265:
244-248). In contrast, IL-4, IL-5 and IL-10 production, which characterizes
the Th2 cytokine profile, increases with HIV disease progression (Clerici
et al. 1993 loc. cit., M Clerici et al. 1996 AIDS Res Hum Retrov
12: 1053-1061). However, this matter is still controversial since C
Graziosi et al. (1994 Science 265: 248-252) could not describe this
shift in the cytokine secretion. These authors reported low levels of IL-2
and IL-4 production, but high levels of IL-10 and INF-g, in patients in
different stages of the disease.
We investigated the cytokine secretion patterns of PBMC from a series of
Brazilian HIV infected patients in response to the mitogen
phyto-hemagglutin (PHA). We collected supernatants of BMC cultures from a
total of 61 HIV-patients followed at the Immunology Division, Hospital das
Clinicas, Faculdade de Medicina, Universidade de Sao Paulo (Hong et al.
unpublished results). Cytokine levels were measured by commercial EIAs.
Similarly to data from Graziosi et al. (loc. cit.), we were not able
to verify a clear Th1 to Th2 pattern shift in our patients. However, we
could observe a decrease in the production of Th1 cytokines, namely IL-2
and INF-g, that paralleled the fall in the immune status of the patients as
assessed by T CD4+ cell counts. Typical Th2 cytokine production, like IL-4,
did not increase with disease progression. This cytokine was almost always
detected at very low levels, in patients and controls, similarly to data
from Graziosi et al. (loc. cit.). Our results, therefore, point out
the suggestion that many of the observed changes in the immune parameters
are rather the consequence than the cause of the disease progression and
immune destruction by the infection.
This suggestion is partially reinforced by our results of IL-10 production.
This cytokine was increasingly produced in HIV infected patients. However,
we interpret this result not as a shift to a Th2 pattern, but as an
increased production of this cytokine by monocytes/macrophages, probably
secondary to the enhanced immune activation status of HIV infected
patients. Thus, monocytes and macrophages would be responsible for the
major part of the synthesis of this cytokine, since they are severely
affected only in late phases of the disease (TR Mosmann & KW Moore 1991
Immunol Today 12: 49-53, E Hagiwara et al. 1996 AIDS Res Hum
Retrovir 12: 127-133). Indeed, we also observed an increased
spontaneous IL-10 production by PBMC from patients compared to controls. In
addition, we routinely detect high serum levels of immunoglobulin A in our
patients (LFM Brigido 1990, Imunodisfuncao Associada a Infeccao pelo
Virus da Imunodeficiencia Humana, Faculdade de Medicina da
Universidade de Sao Paulo, Sao Paulo, 75 pp., F Cavallin 1996 Clin
Immunol Immunopathol 81: 224-228), an immunoglobulin class whose
synthesis is also driven by IL-10.
In this regard, we also evaluated another important cell subset in HIV
infection, the NK cell subset, that presumably is preserved during disease
progression (DE Nunes et al. unpublished results). These cells present
broad specificity, rapid activation and dual role in cell-mediated
cytotoxicity and lymphokine production. In contrast to lymphocytes involved
in specific (acquired) immunity, i.e., T and B cells, NK cells possess an
apparently innate ability to respond to tumors and intracellular pathogens,
such as viruses (G Trinchieri 1989 Adv Immunol 47: 187). There are
controversial reports on the role of the NK cells in the HIV/AIDS
pathogenesis. Some investigators reported that NK cells did not show any
protective effect during HIV disease progression (Q Cai et al. 1990 J
AIDS 3: 669-676) and others have shown that NK cells may represent a
protective tool to avoid HIV infection or disease progression (PF Hu et al.
1995 J AIDS 10: 333-340, B Lucia et al. 1995 Cytometry 22:
10-15).
We evaluated NK cell activity from 41 HIV infected-patients against the
murine mieloma derived cell line K562 labelled with Chromium 51, as
described by Cai et al. (loc. cit.). Our results showed that only
patients with advanced disease presented a decrease in the NK cell
activity.
Literature in this subject is also conflicting. Data for both early and
delayed compromise of NK cell function has been presented (Hu et al.
loc. cit., H Ullum et al. 1995 J Exp Med 182: 789-799, Lucia
et al. loc. cit.). An interesting additional observation, although
still preliminar, was made from the assays with cells from patients in
advanced disease but on regular antiretroviral therapy. Compared to those
not taking this medication, there was a clear improvement of the NK
function. This observation argues for a role of these cells in disease
progression. A similar observation was made by DT Harris et al. (1987 J
Immunol 138: 889-894) showing that a decrease in viral load was
associated with improvement in NK cell activity. This hypothesis will now
be tested, by studying patients on more effective antiretroviral therapies
with concomitant dramatic decreases in the viral load.
The most plausible explanation for the depression in NK cell activity in
late disease may relate to some cytokines, such as INF-a, that play a role
in the regulation of this activity. In fact, INF-a is important in the
activation of NK cells, and its production also is only affected in the
late phase of the disease (DM Howell et al. 1993 J AIDS 6: 15-23).
In conclusion, our results indicate that the monitoring of in vitro
PBMC cytokine production may serve as a parameter of disease progression,
since it reflects the evolution of the disease itself, rather than explain
its immunophatogenesis. Additionally, we also believe that the role of
other immune cell functions, like NK cell activity, deserve further studies
in order to better understand the progression of the HIV infection.
Acknowledgements: to Simone Salomao and Valeria Waikim for technical
assistance.
Supported by grants from the Ministry of Health, Brazil, PN-AIDS/DST, PNUD
038/94; FAPESP 90/4798-3; LIM-56 HC/FMUSP.
Copyright 1998 Fundacao Oswaldo Cruz - Fiocruz
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