Even though T-cell-directed trials have been of limited success, is there reason for optimism? (original) (raw)

Nature Clinical Practice Rheumatology volume 2, pages 58–59 (2006)Cite this article

It has been proposed that rheumatoid arthritis (RA) is a disease of dysregulated T-cell function.1 This is an important hypothesis, as animal models of allotransplantation and human autoimmune diseases have shown that by manipulating T-cell activation mechanisms, not only can a prolonged therapeutic benefit be induced, but also a permanent state of unresponsiveness, known as tolerance. T-cell tolerance can be induced by a variety of mechanisms including deletion of disease-causing T-cell clones, anergy or failure of response of such T cells, deviation of disease-causing type 1 T-HELPER LYMPHOCYTES (TH1) to nonpathogenic cells (TH2), and the induction of regulatory cells that inhibit the action of disease-causing T cells. A number of experimental approaches have been used to investigate and exploit these mechanisms for therapeutic effects in both human and animal model systems. The application of this knowledge to human disease is still in its infancy. The task at hand is undoubtedly complex, difficult and potentially hazardous because of the pivotal role of T cells in adaptive immune responses, without which our existence as free-living organisms would be compromised. The prize, however, is so valuable that researchers must persevere in this endeavor.

The success of anti-tumor-necrosis-factor biologic therapies has put the need for and, indeed, the relevance of, developing anti-T-cell therapies in doubt. Improvements have been observed in some patients receiving these therapies; however, these improvements are only maintained whilst treatment is administered and cessation of therapy leads to flare of the disease. This response has been predicted since it was known that the underlying mechanism that drives rheumatoid inflammation, the T cell, is still active.2 This effect will also apply to other therapies that are directed at distal events in the inflammatory cascade, such as inhibition of interleukin-6, interleukin-1 and others. The fact that such expensive therapies will have to be continued, possibly for the lifetime of the patient, will impose a considerable financial burden on health systems and perhaps lead to the development of serious adverse events. The rational choice, therefore, is to manipulate the T-cell response by inducing an unresponsive state so that treatment is either infrequent or given as a single course at the beginning of therapy.

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  1. Arthritis Research Campaign Professor of Rheumatology at the Department of Rheumatology, Guy's Hospital, King's College London School of Medicine at Guy's, King's College and St Thomas' Hospitals, London, UK
    Gabriel S Panayi

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  1. Gabriel S Panayi
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Correspondence toGabriel S Panayi.

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Panayi, G. Even though T-cell-directed trials have been of limited success, is there reason for optimism?.Nat Rev Rheumatol 2, 58–59 (2006). https://doi.org/10.1038/ncprheum0094

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