Role of DARC in the (PD/PD) regulation of chemokines in man

The Duffy (Fy) antigen receptor complex (DARC) is the red cell receptor for the malaria-causing protozoan Plasmodium vivax and a highly promiscuous chemokine binding protein, specific for some but not all CC and CXC chemokines, such as interleukin-8 and basic monocyte chemotactic protein-1 (MCP-1). Several animal and human studies indicate that DARC may regulate the baseline plasma levels of theses chemokines as well as their pharmacokinetics. Further DARC knock-out mice have increased inflammation following challenge with endotoxin. Many African Americans lack the expression of DARC on red blood cells, which could potentially contribute to ethnical differences in the pathogenesis of various diseases including renal transplant rejection and to the increased lethality of sepsis in this ethnic population. Hence, it is planed to investigate for the first time in humans the effects of DARC expression on the pharmacokinetics and pharmacodynamics of the model chemokine (MCP-1). For this purpose White (Fy positive) and African American (Fy negative) individuals will be recruited into a clinical pharmacology study. The PK/PD of exogenous MCP-1 will be compared between these groups of subjects. Additionally, it is planed to corroborate the data obtained with exogenous MCP-1, by examining the differences in the time course of endogenous DARC binding chemokines after endotoxin challenge between the same ethnical strata. It is expected that these studies will help to elucidate a biological basis for ethnical differences in various diseases in which DARC binding chemokines may play pathogenic role.