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Severe combined immunodeficiency, interleukin-2 (IL-2), and the IL-2
receptor: experiments of nature continue to point the way [see comments]
SD Voss, R Hong and PM Sondel
Department of Pediatrics, University of Wisconsin Medical School, Madison
53792.
The recent discovery of molecular defects in three forms of X-linked
immunodeficiency has quickly transformed the study of immunodeficiency into
one of the most exciting in basic and clinical immunology. The
identification of defects in the IL-2R gamma chain in the etiology of X-
linked SCID has suggested a heretofore unanticipated functional role of the
gamma chain in immunologic development. While new and novel cytokines and
cytokine receptors continue to be identified, it has become clear that our
knowledge of IL-2, one of the best understood cytokine/receptor systems, is
far from complete. Clarifying the molecular interactions between IL-2 and
its receptor complex will improve the sophistication with which these
interactions are manipulated in the clinic for the treatment of autoimmune
disorders and allograft rejection, treatment of lymphoid malignancies, and
cytokine- based therapies for immunotherapeutic treatment of nonlymphoid
cancers. Recent gene therapy approaches to the treatment of children with
the ADA-deficient form of SCID offers yet another exciting path for
investigation. The use of retrovirally infected cord blood hematopoietic
progenitor cells in attempts to reconstitute the immune system of
ADA-deficient SCID children with ADA-producing cells raises the possibility
of similarly "correcting" the defect in X-linked SCID. Such approaches
almost certainly loom on the near horizon for other diseases. However, in
view of the complexity and potentially pleiomorphic nature of defects in
the IL-2R gamma chain, both in terms of their identification and
correction, gene therapy for treatment of X- linked SCID will require a
thorough understanding of the molecular nature of the respective defects.
Effective therapy will require precise knowledge of the defects, in terms
of their influence on the ligand, receptor, and signaling apparatus, as
well as their potential effects on cells of multiple lineages. However,
these caveats aside, the potential for understanding and correcting a
disease that robs infants at so early an age of the potential for a normal
life will continue to make these exciting and extraordinarily rewarding
pursuits.
Volume 83,
Issue 3,
pp. 626-635,
02/01/1994
Copyright © 1994 by The American Society of Hematology
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