1758 THE LANCET • Vol 357 • June 2, 2001 EARLY REPORT Summary Background About 1% of white populations are homozygous carriers of an allele of the gene for the CC chemokine receptor 5 (CCR5) with a 32 bp deletion (CCR5Δ32), which leads to an inactive receptor. During acute and chronic transplant rejection, ligands for CCR5 are upregulated, and the graft is infiltrated by CCR5-positive mononuclear cells. We therefore investigated the influence of CCR5Δ32 on renal- transplant survival. Methods Genomic DNA from peripheral-blood leucocytes of 1227 renal-transplant recipients was screened by PCR for the presence of CCR5Δ32. Demographic and clinical data were extracted from hospital records. Complete follow-up data were available for 576 recipients of first renal transplants. Graft survival was analysed by Fisher's exact test and Kaplan-Meier plots compared with a log-rank test. Findings PCR identified 21 patients homozygous for CCR5Δ32 (frequency 1·7%). One patient died with a functioning graft. Only one of the remaining patients lost transplant function during follow-up (median 7·2 years) compared with 78 of the 555 patients with a homozygous wild-type or heterozygous CCR5Δ32 genotype. Graft survival was significantly longer in the homozygous CCR5Δ32 group than in the control group (log-rank p=0·033; hazard ratio 0·367 [95% CI 0·157–0·859]). Interpretation Patients homozygous for CCR5Δ32 show longer survival of renal transplants than those with other genotypes, suggesting a pathophysiological role for CCR5 in transplant loss. This receptor may be a useful target for the prevention of transplant loss. Lancet 2001; 357: 1758–61 See Commentary page 1725 Introduction Progress in human molecular genetics offers the possibility of unravelling the complex genetic basis of many common diseases. 1 Powerful molecular methods can identify single genes influencing predisposition to particular diseases. These developments have improved understanding of the pathophysiology of many disorders, and more specific therapeutic strategies can therefore be used. Renal-transplant rejection is characterised by an interaction of donor kidney cells with recipient mononuclear cells. In this process, there is increased renal expression of chemokines such as RANTES and MIP- 1. 2–4 By use of a RANTES antagonist, adhesion of monocytes to microvascular endothelium can be blocked, resulting in a substantial decrease in vascular injury and tubular damage in experimental renal transplantation in rats. 5 The upregulation of proinflammatory chemokines such as RANTES and MIP-1 is accompanied by infiltration of the graft by mononuclear cells, consisting predominantly of T lymphocytes, monocytes- /macrophages, and occasional eosinophils. 2–4,6 During both acute rejection and chronic transplant dysfunction, many of the infiltrating mononuclear cells express the CC chemokine receptor 5 (CCR5), which mediates the effects of the chemokines RANTES, MIP-1, MIP-1, and others. 7–11 CCR5 is one of a subfamily of G-protein- coupled receptors with seven transmembrane domains. Chemokine receptors are differentially expressed on leucocytes and various other cell types, and in combination with their ligands they have a central role in leucocyte trafficking. 12–14 The available data suggest that the interaction of RANTES with its receptors, and especially CCR5, is important in transplant rejection. A non-functional mutant allele of CCR5 with an internal deletion of 32 bp (CCR5Δ32) is found with high frequency in Europe and North America. 15–17 Heterozygosity for this allele is found in 10–15% and homozygosity in about 1% of white populations. 18–20 Because CCR5 is the major coreceptor for M-tropic HIV1 strains, individuals homozygous for CCR5Δ32 are highly resistant to HIV infection. 15–17,21 CCR5Δ32 homozygotes appear healthy, and apart from their resistance to HIV1 infection, they show no obvious phenotype. CCR5Δ32 has been associated with a low risk of asthma. 22 The observations of CCR5-positive T-cell infiltration and RANTES upregulation in transplant dysfunction led to our hypothesis that RANTES-mediated recruitment of mononuclear cells during rejection is impaired in individuals lacking a functional CCR5. Such individuals might therefore show less inflammatory response and improved graft survival after renal transplantation, a hypothesis explored by this observational pilot study. Methods Patients We screened 1227 patients presenting to transplant clinics or dialysis units at six European centres between January, 1998, and March, 2000. The patients gave informed CC chemokine receptor 5 and renal-transplant survival Michael Fischereder,* Bruno Luckow,* Berthold Hocher, Rudolf P Wüthrich, Uwe Rothenpieler, Helmut Schneeberger, Ulf Panzer, Rolf A K Stahl, Ingeborg A Hauser, Klemens Budde, Hans-H Neumayer, Bernhard K Krämer, Walter Land, Detlef Schlöndorff Early report *Both investigators contributed equally to the work presented in this report Medizinische Poliklinik, Klinikum der Universität München, München (M Fischereder MD, B Luckow PhD, U Rothenpieler MD, Prof D Schlöndorff MD); Nephrologie, Charité, Universitätsklinikum der Humboldt-Universität, Berlin, Germany (B Hocher MD, K Budde MD, H-H Neumayer MD); Nephrologie, Universitätsspital, Zürich, Switzerland (R P Wüthrich MD); Abteilung für Transplantationschirurgie, Klinikum der Universität–Großhadern, Ludwig-Maximilians-Universität, München (H Schneeberger, Prof W Land MD); Abteilung für Nephrologie/Osteologie, Medizinische Universitätsklinik und Poliklinik, Universität Hamburg, Hamburg (U Panzer MD, R A K Stahl MD); Klinik und Poliklinik für Innere Medizin II, Klinikum der Universität, Regensburg (M Fischereder, B K Krämer MD); and Medizinische Klinik IV, Universität Erlangen-Nürnberg, Erlangen, and Medizinische Klinik IV, Funktionsbereich Nephrologie, Klinik der J W Goethe–Universität, Frankfurt, Germany (I A Hauser MD) Correspondence to: Prof Detlef Schlöndorff, Medizinische Poliklinik, Klinikum der Universität München, Pettenkoferstraße 8a, D-80336, München, Germany (e-mail: sdorff@pk-i.med.uni-muenchen.de)