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Department of Pathology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania.
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: hancock{at}email.chop.edu
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 well-documented 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 CCR3 or CCR4 (5) and CX3CR1 (11), have no effect on the tempo of allograft rejection, despite the intragraft expression in the latter case of respective receptor and ligand, emphasizing the need to do more than simply demonstrate the presence of a receptor/ligand combination before implicating that pathway as a mediator of acute rejection. By contrast, studies with appropriately documented neutralizing but nondepleting mAb, as well as knockout mice, show that targeting of CCR5 (7), expressed by activated T cells and macrophages and especially CXCR3 (12), expressed by activated T and NK cells, has a profound effect on allograft survival.
Third, the effects of concomitant immunosuppression can modulate some of the rather black-and-white outcomes of chemokine receptor targeting in otherwise untreated mice. Thus, use of a subtherapeutic regimen of cyclosporine A (CsA) has a synergistic benefit with targeting of chemokine receptor, which by itself has only a weak (e.g., CCR1) or negligible (e.g., CX3CR1) benefit (8,11) and can lead, at least in the case of CCR1 -/- mice, to permanent engraftment with generation of regulatory CD4+ T cells, which can be adoptively transferred (8). Hence, once again, data from the mechanistic studies in mice can suggest certain lines of investigation for potential clinical benefit, identifying key targets and allowing testing of combination therapies, but the translation to clinical transplantation is still only in its earliest stages. In the case of the chemokine receptor with the most impressive experimental data as to its role in allograft rejection, expression of CXCR3 and its ligands is closely associated with acute rejection clinically (13,14). Studies of the effects of targeting CXCR3 with a humanized anti-CXCR3 mAb are underway in a nonhuman primate renal allograft model, as is use of a CCR5 small molecule antagonist, but there are no data as yet concerning whether targeting of either pathway will be as important clinically as it appears to be experimentally.
A very recent stream of data concerning chemokines and transplant biology, complementary to the animal studies, has arisen through analysis of the effects of chemokine and chemokine receptor polymorphisms on clinical allograft survival; some reports are currently only in abstract form, whereas others have been published. Most genes have multiple polymorphisms, and several chemokine and chemokine receptor nucleotide substitutions and deletions promote resistance to HIV infection through altering expression of requisite viral co-receptors. This has led investigators across the field of clinical medicine to seek evidence of the biologic effects of chemokine and chemokine receptor polymorphisms on the outcomes of diseases from tumors to hypertension, and from asthma, diabetes, and various inflammatory diseases to infectious diseases as diverse as Chagas disease and tuberculosis. What one could do with such information isn’t always unclear. By contrast, allograft recipients are intensively monitored, have ongoing immunosuppression, and still develop allograft-related as well as regular transplant-unrelated diseases, such that they are in some ways an ideal cohort for analysis and, potentially, therapeutic intervention.
The field began with a German report of the effects of 32-bp deletion in the CCR5 gene (CCR5
32) on renal allograft survival; approximately 1% of Caucasians are homozygous carriers of CCR532, leading to an inactive receptor. Analysis of 1227 transplant recipients, with a median follow-up of over 7 yr, showed that patients homozygous for CCR532 had enhanced long-term survival versus heterozygous or wild-type patients (P < 0.05). Though consistent with the experimental data arising from use of CCR5 knockout mice as allograft recipients, as well as the results of anti-CCR5 mAb therapy in wild-type recipients, John Sullivan (15) has pointed out that along with decreased leukocyte recruitment as a result of a genetic lack of CCR5, production of anti-CCR5 antibodies in the CCR532 recipient may also contribute to the beneficial effect of this genotype.
The current paper by Abdi et al. (2), provides data from 163 renal allograft recipients concerning the extent to which chemokine and chemokine receptor polymorphisms can affect the incidence of acute renal allograft rejection. Whereas polymorphisms around CX3CR1 had no effect, positive data involving CCR5 and CCR2 were noted, in each case as predicted from the rodent data. No patients with the rare CCR532 homozygosity were identified so that the work does not directly overlap with the findings of the German report. However, patients homozygous for another CCR5 polymorphic allele, CCR5–59029-A, had about a twofold reduction (P < 0.05) in the incidence of acute rejection, whereas those with the CCR5–59029-G had an increased rate of acute rejection (P < 0.05).
The protective effects of CCR5–59029-A homozygosity may be, as Abdi et al. indicate, counterintuitive. The authors cite data that CCR5–59029-A homozygosity is associated with increased promoter activity (16) and enhanced, rather than decreased, CCR5 expression by CD4+ T cells (17). However, knowledge of the biology of this polymorphism is still fragmentary, with the effect on CCR5 promoter activity only being established using a reporter gene system (16), and the phenotypic data coming from flow cytometric analysis of a small number of Chinese volunteers (17). There are known to be racial differences in the incidence of CCR5 polymorphisms; the extent of the increase was only 2 to 3%, and only resting T cells were studied. Whether the increased CCR5 expression noted might reflect differences in the activation state of different individuals, and indeed, the extent of correlation between this polymorphism and CCR5-dependent functional chemotactic responses have not been determined. Hence, the basis for the effect of this polymorphism is far from clear and may also have its downside, as shown by the recent association of the CCR5–59029-A homozygous state with an increased risk of diabetic nephropathy (18). Likewise, the beneficial effect of possessing even one CCR2–64I allele (P < 0.05) is not easy to understand because this polymorphism does not alter CCR2 expression or function; its complete linkage disequilibrium with CCR5–59029-A may be at least partly responsible. At 3 yr of follow-up, renal function did not differ significantly between any of the tested genotypes, but this may reflect various factors as noted by the authors.
Given the extensive documentation and monitoring of transplant recipients overall, many future studies of this type can be anticipated. Questions as to the importance of specific alleles (e.g., one or more of the CCR5 polymorphisms) to graft rejection and long-term survival and function; and differences in the importance of a given polymorphism according to the organ being transplanted, as suggested by the third paper in which CCR2–64I was not associated with any beneficial effect on acute rejection or long-term liver allograft survival (3), may well only be answerable by much larger studies involving collection of registry or other multicenter data over longer periods. It is likely that only such large-scale studies will be able to assess the significance of the recently identified and apparently very rare polymorphisms of CXCR3 (19).
Lastly, the clinician’s options to take advantage of the accruing data from studies of chemokines and chemokine receptors in transplant recipients are far from clear. Clinical trails of mAb or small molecules to block some of the key pathways are likely to be years away, even assuming clear successes in nonhuman primate trials, and Big Pharma has begun to shrink from developing new therapies for the transplant field as the 1-yr survival rates continue to rise and the rates of acute rejection fall. Some benefit may be attained from expanded use of chemokines and their receptors as markers in the molecular or immunohistologic assessment of transplant biopsies (13). However, perhaps the most interesting, novel, and rapidly developing application may be use of the chemokine polymorphisms as part of a pharmacogenomics approach. The field of pharmacogenetics, involving studies of specific sequence variations in candidate genes suspected of affecting drug responses, has contributed important information concerning the role of gene polymorphisms to the response of transplant recipients to therapy with CsA, azathioprine, corticosteroids, and other agents (20). Pharmacogenomics takes a supposedly more genome-wide approach to drug development on the basis of inherited differences in responses to drugs, but it is clearly closely related to pharmacogenetics. Regardless of the term used, analysis of the role of chemokine and chemokine receptor polymorphisms may lead to reduction in immunosuppression in selected patients, with associated decreases in drug toxicity (21). Despite claims of some of the most ardent advocates of pharmacogenomics, this approach may not necessarily directly decrease costs associated with the management of transplant recipients, even given lower rates of drug toxicity, but it should lead to a better quality of life and enhanced long-term organ function. Thus, as so often is the case in modern medicine, it is likely that research into transplant immunobiology, spanning basic and clinical science and using cutting-edge molecular and other approaches, will lead to the development of novel therapeutic approaches, which will eventually extend far beyond the transplant community.
References
This article has been cited by other articles:
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  R. Langer, M. Wang, S. M. Stepkowski, W. W. Hancock, R. Han, P. Li, L. Feng, R. A. Kirken, K. L. Berens, B. Dupre, et al. Selectin Inhibitor Bimosiamose Prolongs Survival of Kidney Allografts by Reduction in Intragraft Production of Cytokines and Chemokines J. Am. Soc. Nephrol., November 1, 2004; 15(11): 2893 - 2901. [Abstract] [Full Text] [PDF]
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