Grants and Contracts Details
Description
The anemia of chronic disease (ACD) is one of the most common hematologic syndromes encountered in clinical medicine. Over the
last decade, studies have clearly established that ACD is a consequence of the cytokines which mediate the immune and
inflammatory process. In contrast, sickle cell anemia is the result of a genetic defect producing a single amino acid change which
alters the solubility of deoxygenated hemoglobin. Over the same period of time, it has become recognized that the clinical
manifestations of the sickle syndromes result nom a constellation of processes, including activation of inflammation. A heightened
inflammatory state with consequent cytokine production can be demonstrated in patients with sickle cell disease. However, the
unique characteristics of the sickle erythrocyte (including the persistent expression ofCD36) alter the characteristics of the erythroid
response to cytokines. Review of the literature suggests that CD36 persistence at high levels is unique to sickle erythrocytes, and
contributes to their adhesive properties. [n our preliminary data, we have demonstrated that CD36 is a positive regulator of
erythropoiesis. As discussed above, the cytokine mediators of the inflammatory response produce ACD, and similar mechanisms can
be implicated in sickle disease. Based on data in the literature and on our preliminary results reported below, it is hypothesized that
..
CD36 expression protects sickle erythroid progenitors against cytokine suppression, and that those progenitors. which persistently
express CD36 have a selective growth advantage in the presence of inhibitory cytokines. This would result in the preferential
production of CD3Hxpressing erythrocytes, which are then more likely to participate in intravascular adhesion. The cytokines
involved in the inflammatory response would therefore enhance theftequency ofvascular sickling events by increasing the ftequency
of potentially adherent erythrocytes. This hypothesis will.be testcdthrough the following Specific Aims: Specific Aim I will identitY
the differences in CD36 cxptessionbetween progenitorsftom sickle cell patients and precursors, and those ftom controls. In Specific
Aim 2, the differences in sensitivity to cytokine inhibition between sickle and control CFU-E, and the extent to which these
differences can be attributed to differences in CD36 expression, will be defined. In Specific Aim 3, FA6-152will be used to
characterize the response of CFU-E nom sickle patients to CD36 activation, and to determine how CD36 activation alters the pattern
of progenitor suppression by inhibitory cytokines, as well as the contribution of rhEPO to these processes; and Specific Aim 4 will
characterize local cytokine production in the marrow of sickle cell patients, and how it relates to erythroid CD36 expression and to
clinical phenotype.
Status | Finished |
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Effective start/end date | 9/30/01 → 7/31/07 |
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