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Beneficial effects of targeting CCR5 in allograft recipients
1Transplantation, Millennium Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
Background:
The chemokine receptor, CCR5, and its three high-affinity ligands, macrophage inflammatory protein- (MIP) 1alpha, MIP-1beta, and regulated on activation normal T cell expressed and secreted (RANTES), are expressed by infiltrating mononuclear cells during the rejection of clinical and experimental organ allografts, although the significance of these molecules in the pathogenesis of rejection has not been established.
Methods:
We studied intragraft events in four allograft models. First, we studied cardiac transplants in fully MHC-mismatched mice that were deficient in CCR5 or two of its ligands, MIP-1alpha or RANTES. Second we tested the effects of a neutralizing rat anti-mCCR5 monoclonal antibody on allograft survival. Third we assessed whether a subtherapeutic course of cyclosporine would potentiate enhance survival in CCR5-deficient recipients. Finally, we tested the effect of targeting CCR5 in a class II-mismatched model.
Results:
Whereas mice deficient in expression of MIP-1alpha or RANTES reject fully MHC-mismatched cardiac allografts normally, CCR5-/- mice, or CCR5+/+ mice treated with a neutralizing mAb to mCCR5, show enhanced allograft survival. MHC class II-disparate mismatched are permanently accepted in CCR5-/- but not CCR5+/+ recipients. Finally, the beneficial effects of targeting of CCR5 are markedly synergistic with the effects of cyclosporine, resulting in permanent engraftment without development of chronic rejection.
Conclusions:
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.
Insights
Targeting the CCR5 receptor significantly enhances organ allograft survival by reducing T cell and macrophage infiltration. Blocking CCR5, especially with cyclosporine, leads to permanent engraftment and prevents chronic rejection.
Area of Science:
- Immunology
- Transplantation Biology
Background:
- The chemokine receptor CCR5 and its ligands (MIP-1α, MIP-1β, RANTES) are present on infiltrating cells during organ transplant rejection.
- Their precise role in allograft rejection pathogenesis remains unclear.
Purpose of the Study:
- To investigate the significance of CCR5 in allograft rejection mechanisms.
- To evaluate CCR5-targeting as a therapeutic strategy for improving transplant outcomes.
Main Methods:
- Studied cardiac allografts in CCR5-deficient mice and mice lacking CCR5 ligands (MIP-1α, RANTES).
- Administered a neutralizing anti-CCR5 monoclonal antibody to assess its impact on allograft survival.
- Examined the synergistic effects of CCR5 deficiency and subtherapeutic cyclosporine treatment.
- Investigated CCR5 targeting in a MHC class II-mismatched allograft model.
Main Results:
- Mice deficient in MIP-1α or RANTES showed normal allograft rejection.
- CCR5-deficient mice and those treated with anti-CCR5 antibody exhibited enhanced allograft survival.
- MHC class II-disparate allografts were permanently accepted in CCR5-deficient recipients.
- Targeting CCR5 synergized with cyclosporine, leading to permanent engraftment and preventing chronic rejection.
Conclusions:
- CCR5 is crucial for recruiting host T cells and macrophages, driving allograft rejection.
- Targeting CCR5 presents a promising therapeutic avenue for preventing organ transplant rejection.
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