Chemokines transplant rejection

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. 

Horuk R, Clayberger C, Krensky AM, et al. A non-peptide functional antagonist of the CCR1 chemokine receptor is effective in rat heart transplant rejection. J Biol Chem 2001 276 4199-4204. 

Segerer S, Cui Y, Eitner F, et al. Expression of chemokines and chemokine receptors during human renal transplant rejection. Am J Kidney Dis 2001 37 518-531. 

Pattison J, Nelson PJ, Huie P, et al. RANTES chemokine expression in cell-mediated transplant rejection of the kidney. Lancet 1994 343 209-211. 

Segerer S, Regele H, Mack M, et al. The duffy antigen receptor for chemokines is up-regulated during acute renal transplant rejection and crescentic glomerulonephritis. Kidney Int 2000 58 1546-1556. 

Based on their broad range of fimctions, the chemokines are easily deduced to be important players in diseases characterized by inflammation and cell infiltration, such as asthma, atherosclerosis, rheumatoid arthritis, multiple sclerosis, colitis, Crohn s disease, experimental autoimmune encephalomyelitis (EAE), and psoriasis, among others (8). Finally, CXCR4 and CCR5 are the two main coreceptors for HIV-1 infection (9)., some chemokine receptors also participate in tumor metastasis (7) and transplant rejection (10). 

In summary, the above human studies have demonstrated the importance of chemokines/chemokine receptors in transplantation rejection (Table 1). Furthermore, translational studies in animal models of allograft rejection have demonstrated proof of the principle that chemokines and their interaction with their cell... 

Fig. 1. Various ways chemokines might accelerate transplant rejection. Release of chemokines from the transplanted organ and/or cells infiltrating the graft may result in shifting the TH-l/TH-2 cytokine balance and cell activation that lead to further chemokine release and continued cell reemitment. Collectively these changes lead to tissue damage, graft arteriosclerosis, and eventually graft dysfunction.

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). 

Pattison, J., Nelson, P. J. Huie, P., von Leuttichau, 1., Farshid, G., Sibley, R. K., and Krensky, A. M. (1994) RANTES chemokine expression in cell-mediated transplant rejection of the kidney. Lancet. 343,209-211. 

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. 

Key Words Allograft transplantation chemokine receptor acute rejection chronic rejection CCR1 CCR5 CXCR3 CXCR1 CXCR2. 

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