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Shift Rift: Series of Research Papers Take To Task Would-Be Discoverers Of Cytokine Switch
Scrutinizing the Knock-out Mice

August 1994

It was the big story out of Amsterdam, summer of 1992. Later that fall at the Vth International Vaccine Cooperative meeting in Chantilly, VA, it gave birth to Jonas Salk's highly publicized "Reconceptualization of the Basic Immune Correlates Required for Protection from an HIV-1 Vaccine" where the polio pioneer announced that antibodies would not protect but that CMI (cell-mediated immunity) was the key to developing effective prophylactic HIV vaccines. Conveniently, it also helped to explain the apparent short-comings of his antibody-based approach. It even held up a UCLA clinical trial of interleukin-4 (IL-4) as investigational therapy for Kaposi's. Proponents of the theory warned those running the trial that giving one of the "bad" cytokines (IL-4, IL-5, IL-10) to patients with HIV would tip the balance and hurtle them non-stop towards an antibody dominated immune response and straight on to death.

As first unveiled by NIH and NCI researchers Gene Shearer and Mario Clerici, the bedazzling hypothesis became known as the "TH1-TH2 shift," and as recently as last summer everyone was buzzing about it. In a vacuum forged of treatment quandaries and failed paradigms, the TH1-TH2 dogma offered itself up as something of a life raft to frustrated researchers and lay observers alike, flailing to find direction in a flooding torrent of dispelled dogma.

As presented by Drs. Shearer and Clerici before a series of riveted audiences, the phenomenon seemed rather straightforward. An analysis of circulating cytokines (tiny protein messages) early on in HIV infection showed a surplus of IL-2 and interferon gamma, cytokines associated with a TH1-type dominated (or cell-mediated) immune response. But in the blood of persons in the late stages of HIV infection, IL-2 and gamma interferon had all but disappeared. Instead, an abundance of IL-4 and IL-10 were observed, cytokines associated with a TH2-type dominated (or antibody) immune response. The conclusion seemed self-evident, a "no-brainer," as it were: The TH1-type immune response was present during asymptomatic infection while the TH2 configuration signaled clinical deterioration and death. Further studies in "exposed-but-not-infected" high-risk populations who showed strong TH1 immune activity but virtually no TH2, seemed to corroborate such a model. If only the immune system could be persuaded to maintain the TH1, predominantly cell-mediated immune response, the asymptomatic state could be preserved indefinitely -- or so the thinking went.

Based on a paper published in Science by Shearer et al. in 1993 where administration of IL-12 was shown to have restored in vitro cell-mediated immune responses in HIV+ individuals (and to inhibit the development of MAIDS in mice), the TH1/TH2 hypothesis seemed on its way towards clinical validation. Genetics Institute has even launched a small clinical study of IL-12 in human volunteers.

But a series of scientific papers recently published in the July 8 issue of Science report that, despite repeated attempts, independent research teams have been unable to corroborate Clerici and Shearer's original work. Except for a moderate shift -- toward increased numbers of "TH0" clones -- among the T-cell populations responsible for so-called "recall antigens," no conversion to TH2 predominance was observed.

Additional research papers, tucked away among the last pages of the scientific weekly in a section called "Technical Comments," questioned whether experiments with murine acquired immunodeficiency syndrome (MAIDS) in IL-4 deficient mice (which seemed to strengthen the TH1/TH2 shift hypothesis) might have possibly been flawed. The so-called IL-4 "knock-out" mice, specifically bred without the gene for IL-4 and thus apparently impervious to the conversion toward TH2, were reported in 1993 to be resistant to MAIDS precisely because they lacked any IL-4. But rather than the absence of IL-4 accounting for the mice's apparent resistance to disease, it turns out that it might well have been an unintentional genetic difference in the knock-out mice which resulted from the special IL-4 knock-out breeding. Meanwhile, back in Los Angeles, KS volunteers in the IL-4 study were showing decreased viral activity (as measured by ICD p24 antigen assay) as well as a slight improvement in their KS lesions. Once again, the prevailing scientific theory was at a loss to explain the clinical reality.

Doubting Thomases with regard to the TH1-TH2 shift theory all along, Fauci and those in his employ (Celia Graziosi and Giuseppe Pantaleo chief among them) have, over the years, been quite bold in their affront to the TH1-TH2 orthodoxy. In their paper, looking at cytokine expression in lymph nodes of HIV+ patients, they flatly state their finding "no evidence of a shift in cytokine patterns toward the TH2 subset." In a second paper, Italian researchers Enrico Maggi and others report that they too could not corroborate the observation of a bias toward TH2-like cytokine patterns during progression to AIDS, although they concede that differences in methodologies (notably the duration of stimulation periods and the stage of disease of individuals studied) could explain some of the discrepancies in results. "Information obtained from looking at circulating T-cells in the blood," they add (Shearer's original paper), "might present a different picture than would T-cells from lymph nodes" (Graziosi, Pantaleo, Fauci et al.).

This is not to say the TH1-TH2 paradigm has been invalidated -- at least as a model for how differing immune responses can lead to susceptibility to or protection from various pathogens. In other infections, parasitic infections in particular, there is a well-documented dichotomy between these two immune responses. In a study commonly cited by Dr. Salk, conducted with a parasitic disease called Leishmaniasis in mice, a state of resistance is associated with the presence of DTH responsiveness (delayed-type hypersensitivity, an indication of cell-mediated immunity) and the absence of antibody responsiveness. In leprosy, resistance is associated with a predominance of TH1 cells; and susceptibility, with a predominance of TH2 cells. In light of this recent research, where the TH1-TH2 balance fits into the many unanswered pathogenic questions about HIV apparently remains to be elucidated.

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