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 from 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 of CD36) 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. In 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 CD36-expressing erythrocytes, which are then more likely to participate in intravascular adhesion. The cytokines involved in the inflammatory response would therefore enhance the frequency of vascular sickling events by increasing the frequency of potentially adherent erythrocytes. This hypothesis will be tested through the following Specific Aims:
Specific Aim 1 will identify the differences in CD36 expression between progenitors from sickle cell patients and precursors, and those from 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 from 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.
| Dallalio, Gail; Means Jr, Robert T (2008) Placental growth factor attenuates suppression of erythroid colony formation by interferon. Transl Res 152:233-8 |
| Dallalio, Gail; Brunson, Chris Y; Means Jr, Robert T (2007) Cytokine concentrations in bone marrow of stable sickle cell anemia patients. J Investig Med 55:69-74 |
| Dallalio, Gail; Law, Erin; Means Jr, Robert T (2006) Hepcidin inhibits in vitro erythroid colony formation at reduced erythropoietin concentrations. Blood 107:2702-4 |
| Means Jr, Robert T (2004) Hepcidin and anaemia. Blood Rev 18:219-25 |
| Means, Robert T (2004) Hepcidin and cytokines in anaemia. Hematology 9:357-62 |
| Dallalio, Gail; Fleury, Thomas; Means, Robert T (2003) Serum hepcidin in clinical specimens. Br J Haematol 122:996-1000 |
| Means Jr, Robert T (2003) Recent developments in the anemia of chronic disease. Curr Hematol Rep 2:116-21 |
