Transplant rejection chemokine role

Chemokines have been shown to be associated with a number of autoinflammatory diseases including multiple sclerosis, rheumatoid arthritis, atherosclerosis, dermatitis, and organ transplant rejection. Evidence, reviewed below, is mounting that chemokines may play a major role in the pathophysiology of these diseases and thus chemokine receptor antagonists could prove to be useful therapeutics in treating these and other proinflammatory diseases. 

Before examining the potential roles of chemokines in the pathophysiology of transplant rejection, it is important to review the biology that underlies the rejection of solid organ allografts. 

Although studies have been focused on the cell-recruiting activity of chemokines, other properties of chemokines in transplant rejection need to be examined further. Several studies have illustrated an effect of chemokines on the functional activity of cells enhancing either cytotoxicity, T-cell proliferation, or reactive oxygen intermediates (18-20). Recently, a role for chemokines in the regulation of TH-l/TH-2 cytokine responses has been described (21,44). Although it remains controversial, it has been suggested that TH-1 responses may promote rejection (22). 

Part II of the book explores the role of chemokines in a variety of chronic and acute inflammatory diseases, including acute respiratory distress syndrome (ARDS), asthma, interstitial lung disease, rheumatoid arthritis, and organ transplant rejection. These topics are discussed through a presentation of the pathogenesis of the disease, using a wide range of clinically relevant animal models of the disease, as well as the examination of chemokine expression in clinical samples. 

The literature on chemokines in transplantation has been extensively reviewed in recent years (7-9). In this chapter, we focus on a limited number of chemo-kine receptors where evidence for a functional role has been verified. From the plethora of chemokine receptors, this has been demonstrated for CXCR1/2 in reperfusion injury and for CCR1, CCR5, and CXCR3 during acute and chronic allograft rejection. 

Acute rejection usually occurs within the first year after transplantation and is characterized by an intense cellular immune response within the graft. Acute rejection can usually be treated effectively with anti-inflammatory and anti-T-cell therapies. However, recurrent episodes of acute rejection may result in graft destruction or may lead to the development of chronic rejection. Chronic rejection usually occurs years after transplantation and is manifested by progressive loss of graft function, arteriosclerosis, and fibrosis. Whereas the pathogenesis of chronic rejection is not clear, both immunological and nonimmunological mechanisms seem to be involved (7). Based on the available data, chemokines are most likely to play a role in acute and chronic rejection as indicated schematically in Fig. 1. 

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