Chemokines and transplant immunobiology.

The importance of showing up at the right place at the right time is instilled in leukocytes, just as it is in each one of us, by our parents. The fact that leukocyte infiltration of a newly established allograft typically presages the development of acute rejection is the downside of having an exquisitely tuned and finely balanced immune system. Chemokines binding to their receptors on leukocytes mediate the behind-the-scenes plays between antigen-presenting cells and host T cells in lymphoid tissues, the actual here-and-now, in-your-face fulminant immune responses that can acutely destroy a graft, and also, as seems increasingly apparent, smoldering inflammatory responses seen clinically as chronic rejection. Given these complex and multifaceted roles, knowledge of chemokine biology is no longer just for the aficionado. Indeed, genetically based differences in chemokine-dependent responses may be yet another thing for which to blame (or thank) our parents, as evidenced by clinical studies of the effects of chemokine and chemokine receptor polymorphisms on allograft rejection and allograft survival (1–3). Excellent reviews of chemokine biology are available, including one by Murphy et al. (4), one of the authors of the accompanying paper (2), which is available for free at the Journal’s web site (www.pharmrev.org). People are often put off by the complexity and nomenclature associated with chemokines, especially as there are standard names, a systematic nomenclature developed by Dr. Philip Murphy, Albert Zlotnik, and Osama Yoshie and others, and now even an additional Leukocyte Workshop-derived cluster of differentiation (CD) terminology. However, the current paper by Abdi et al. (2) avoids the systematic but bland nomenclature in favor of the older happily descriptive efforts; therefore, this commentary will as well. Focusing on the surface membrane-bound chemokine receptors of leukocytes allows us to quickly note the array of potential interactions, though receptor expression is a dynamic process with certain receptors involved in homeostatic recirculation through tissues and others, induced by cytokines, oxidative stress, lipopolysaccharide, or other stimuli, which are important to the directed migration and functions of activated leukocytes. Chemokine receptors have adjacent amino-terminal cysteines (C) (there are currently ten welldocumented CC chemokine receptors), adjacent cysteines with a single interposing other (X) amino acid (there are now at least seven CXC chemokine receptors), or three interposing amino acids (CX3C), and there is one example of a chemokine receptor with only a single cysteine among the initial dozen amino-terminal residues. Over the last decade, a large number of reports of chemokine or chemokine receptor expression in the context of clinical or experimental allograft rejection were published. However, there are often numerous ligands for a given chemokine receptor, and a specific chemokine may typically bind to two or more receptors; therefore, analysis of whether a given chemokine receptor plays a significant role in the (15) allograft response has become increasingly important (5,6). To this end, studies of knockout mice, especially when teamed with use in wild-type mice of blocking monoclonal antibodies (mAb) to the corresponding receptor, have provided the first hard data as to what all the complexity of chemokine biology might mean to the highly practical in vivo world of transplantation. These types of mechanistic studies are necessarily reductionist because, in essence, the question regards whether this chemokine or its receptor have a statistically significant effect on allograft survival in heterotopic allograft models, which are far from clinically relevant but do yield data of direct significance to understanding mammalian immune responses to a transplant? Moreover, this work has primarily focused to date on the unmodified acute rejection of cardiac allografts by unsensitized recipients, such that different outcomes may be anticipated in the context of islet or other cellular or tissue allografts when using other solid organs or in models in which acute rejection is prevented or attenuated to the extent that chronic rejection can then be analyzed. Several important points have emerged so far from these in vivo-based mechanistic studies. First, targeting of a single chemokine is typically (though not always) ineffective in prolonging allograft survival. An example of this general principle is the lack of efficacy in targeting of macrophage inflammatory protein–1 or RANTES (7), whereas targeting of their receptors, CCR1 (8) and CCR5 (7), is of therapeutic significance. However, an interesting exception arises in the case of the chemokine, IP-10 (9), because this is induced rapidly posttransplantation within donor endothelial cells and promotes recruitment and activation of host NK and T cells expressing the corresponding receptor, CXCR3. Second, chemokine receptors differ in their importance as targets in alloresponses. Thus, chemokine receptors such as CCR1 and CCR2 primarily promote macrophage recruitment to an allograft, such that their targeting in knockout mice has only a modest effect on graft survival (8,10). Moreover, the presence or absence of some chemokine receptors, such as Correspondence to: Dr. Wayne W. Hancock, Department of Pathology, 807B Abramson Research Center, The Children’s Hospital of Philadelphia, 3615 Civic Center Blvd., Philadelphia, PA 19104-4318. Phone: 215-590-8709; Fax: 215-590-7384; E-mail: [email protected]