Beneficial Effects of Targeting Ccr5 in Allograft Recipients1

Gao, Wei; Kerrie, L.; Csizmadia, Vilmos; Smiley, Stephen T.; Soler, Dulce; King, Jennifer; Danoff, Theodore M.; Hancock, Wayne W.

doi:10.1097/00007890-200110150-00003

Cited by 153 publications

(146 citation statements)

References 18 publications

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“…These observations reveal a novel phenotype in Ccr5 À/À mice favoring alternative activation of macrophages. This finding may account for the improved transplant survival described in Ccr5-deficient mice [12][13][14][15], in primates treated with CCR5 antagonists [33] and in humans homozygous for the CCR5D32 allele [8]. Furthermore, this observation may prove to be of considerable significance for the progression of chronic inflammatory and fibrosing disease processes.…”

Section: Discussionmentioning

confidence: 87%

“…Initially, cardiac [12,13], islet [14,15] and carotid artery [12] transplantation models were performed. In these experiments, Ccr5 deficiency of the recipient had a beneficial effect on the transplant and led to modest prolongation of graft survival.…”

Section: Discussionmentioning

confidence: 99%

“…Phenotypic alterations in these mice have been analyzed in different transplant models including experimental cardiac, carotid artery, islet, and renal allografts [12][13][14][15][16][17][18]. Kidney transplantation represents the most frequent organ replacement therapy in humans, but despite major advances in the treatment of acute rejection, long-term graft survival has not markedly improved.…”

Section: Introductionmentioning

confidence: 99%

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Chemokine receptor Ccr5 deficiency induces alternative macrophage activation and improves long‐term renal allograft outcome

et al. 2009

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The chemokine (C-C motif) receptor 5 (CCR5) has been implicated in experimental and clinical allograft rejection. To dissect the function of CCR5 in acute and chronic renal allograft rejection, bilaterally nephrectomized WT and Ccr5 À/À C57BL/6 mice were used as recipients of WT BALB/c renal allografts and analyzed 7 and 42 days after transplantation. Lesion scores (glomerular damage, vascular rejection, tubulointerstitial inflammation) and numbers of CD4 1 , CD8 1 , CD11c 1 and alpha smooth muscle actin (aSMA) 1 cells were reduced in allografts from Ccr5 À/À recipients during the chronic phase. Increasing creatinine levels indicated deterioration of allograft function over time. While mRNA expression of Th1-associated markers decreased between 7 and 42 days, Th2-associated markers increased. Markers for alternatively activated macrophages (arginase 1, chitinase 3-like 3, resistin-like a, mannose receptor, C type 1), were strongly upregulated (mRNA and/or protein level) only in allografts from Ccr5 À/À recipients at 42 days. Ccr5 deficiency shifted intragraft immune responses during the chronic phase towards the Th2 type and led to accumulation of alternatively activated macrophages. Additionally, splenocytes from unchallenged Ccr5 À/À mice showed significantly increased arginase 1 and mannose receptor 1 mRNA levels, suggesting constitutive alternative activation of splenic macrophages. We conclude that Ccr5 deficiency favors alternative macrophage activation. This finding may be relevant for other inflammatory diseases that involve macrophage activation and may also influence future therapeutic strategies targeting CCR5.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Chemokine receptor Ccr5 deficiency induces alternative macrophage activation and improves long‐term renal allograft outcome

et al. 2009

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“…We have previously shown that intragraft expression of key chemoattractant pathways, especially involving CXCR3 and CCR5 in the case of fully MHC-disparate allografts, is markedly blunted by CD154/DST costimulation blockade [17][18][19], as is intragraft expression of PD-1 and PD-L1 [12]. We now report that, compared to WT mice, use of costimulation blockade in PD-1 -/-recipients had markedly reduced efficacy, resulting in significantly increased intragraft mRNA levels of IL-2 and IFN-c cytokines, as well as components of the IP-10/CXCR3 and RANTES/CCR5 chemokine/chemokine receptor pathways (Fig.…”

Section: Pd-1 Suppresses Intragraft Gene Expressionmentioning

confidence: 99%

Programmed cell death 1 (PD‐1) and its ligand PD‐L1 are required for allograft tolerance

2007

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Programmed cell death-1 (PD-1, CD279) and its widely expressed, inducible ligand, PD-L1 (CD274), together dampen T cell activation, but whether they are essential for allograft tolerance is unknown. We show, using gene-deficient mice and blocking mAbs in wild-type mice, that costimulation blockade is ineffectual in PD-1 -/-or PD-L1 -/-allograft recipients, or in wild-type allograft recipients treated with anti-PD-1 or anti-PD-L1 mAb. Alloreactive PD-1 -/-CD4 and CD8 T cells had enhanced proliferation and cytokine production compared to wild-type controls, and anergy could not be induced in PD-1-deficient CD4 T cells. We conclude that without inhibitory signals from PD-1 ligation, alloantigen-induced T cell proliferation and expansion cannot be regulated by costimulation blockade, and peripheral tolerance induction cannot occur.

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“…In addition, blocking CCR5 ligands MIP-1a and RANTES inhibit graft rejection in experimental kidney (16) and lung transplant models (17). The deletion of CCR2 and CCR5 prolonged allograft survival compared to wild-type animals in heterotopic Chemokines in Liver Transplantation cardiac transplant models (8,15). The functional importance of CCR5 in renal allograft survival was recently shown by Fischereder et al This study showed that null allele of CCR5 behaves as a major determinant for long-term allograft survival and results in prolongation of the half-life of renal allografts, as compared to the heterozygous or wild-type allele (60 vs. 17 years) (18).…”

Section: Introductionmentioning

confidence: 99%

The Impact of Polymorphisms in Chemokine and Chemokine Receptors on Outcomes in Liver Transplantation

Schröppel

Fischereder

Ashkar

et al. 2002

American Journal of Transplantation

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Chemokines and their corresponding receptors likely play a central role in directing mononuclear cells to the graft sites during rejection. Genes for the chemokine stromal derived factor-1 (SDF1) and CC chemokine receptors CCR2 and CCR5 are characterized by polymorphisms which alter their function. We genotyped DNA of 207 liver transplant recipients by PCR or PCR-RFLP for CCR2-64I, CCR5D32, and SDF1-3ƒA polymorphisms, and examined their association on outcomes in liver allograft recipients. Due to the low number of patients homozygous for CCR2-64I and CCR5D32, only the effects of their heterozygous variants were addressed in this study. None of the investigated polymorphisms showed a significant shift in gene frequency in acute rejection and rejection-free groups, or for graft survival. The gene frequency of the SDF1-3ƒA allele was significantly (p Ω0.034) higher in patients who died (29.0%, n Ω 31) compared to recipients still alive (17.1%, n Ω 172). The mean patient survival time post transplant was 134 months in patients with SDF1 wild-type, significantly (log rank p Ω0.014) longer than 98 months in patients with at least one SDF1-3ƒA allele. The CCR2 and CCR5 polymorphisms were not associated with significant differences in mortality rate. In conclusion, CCR2-64I, CCR5D32, and SDF1-3ƒA genotypes did not influence the risk for acute rejection or graft survival. However, in liver allograft recipients SDF1-3ƒA is significantly associated with higher mortality.

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Beneficial Effects of Targeting Ccr5 in Allograft Recipients1

Abstract: We conclude that CCR5 plays a key role in the mechanisms of host T cell and macrophage recruitment and allograft rejection, such that targeting of CCR5 clinically may be of therapeutic significance.

Cited by 153 publications

References 18 publications

Chemokine receptor Ccr5 deficiency induces alternative macrophage activation and improves long‐term renal allograft outcome

Chemokine receptor Ccr5 deficiency induces alternative macrophage activation and improves long‐term renal allograft outcome

Programmed cell death 1 (PD‐1) and its ligand PD‐L1 are required for allograft tolerance

The Impact of Polymorphisms in Chemokine and Chemokine Receptors on Outcomes in Liver Transplantation

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