RANTES Plays an Important Role in the Evolution of Allograft Transplant-induced Fibrous Airway Obliteration

Abstract

Although lung transplantation is a widely applied therapeutic modality for end-stage pulmonary disease, the long-term survival following this procedure is limited by the development of bronchiolitis obliterans (BO). We investigated the role of RANTES, a C-C chemokine, in the evolution of fibrous airway obliteration (FAO) using a rat heterotopic tracheal transplant model. RANTES was highly expressed in infiltrating mononuclear cells in both allogeneic and isogeneic grafts as revealed by immunohistochemistry. Using a miniosmotic pump, neutralizing anti-RANTES antibody was locally and continuously infused to allografts, whereas recombinant rat RANTES was administered to isografts. Anti-RANTES antibody treatment decreased the number of CD4(+) infiltrating cells in allotracheas and preserved luminal patency compared with those of allocontrols. However, RANTES infusion in isografts did not induce FAO, even though CD4(+) cell migration was increased by this treatment. It appears that RANTES is relevant to the recruitment of CD4(+) cells and the development of FAO in the process of allorejection. Local administration of anti-RANTES might be a therapeutic option for BO following lung transplantation.

CCR1/CCL5 (RANTES) receptor-ligand interactions modulate allogeneic T-cell responses and graft-versus-host disease following stem-cell transplantation

“…[47][48][49] Studies targeting the biologic effects of CCL5 in vivo by using neutralizing antibodies or receptor antagonists have revealed a role for CCL5 in lymphocyte and macrophage recruitment to sites of inflammation and allograft rejection. 24,[50][51][52][53][54][55][56][57][58][59][60][61][62] In addition, we have recently reported that CCL5 expression is up-regulated in the lung after allo-SCT, is associated with elevations in mRNA levels for CCR1, and significantly contributed to the influx of donor cells that characterizes pulmonary injury during the development of idiopathic pneumonia syndrome. 26 In addition to modulating leukocyte recruitment, our data suggest that interactions between CCR1 and CCL5 also contribute to T-cell activation.…”

Therapy with Nonglycosaminoglycan‐Binding Mutant CCL7: A Novel Strategy to Limit Allograft Inflammation

“…+ cells (27), whilst CCL3 (MIP-1a) exacerbates inflammatory bowel disease in a mouse model (28). (29).…”

Post-transplant bronchiolitis obliterans

“…CC as well as CXC chemokines and their receptors play an important role in the recruitment of intragraft leukocytes. RANTES (regulated upon activation, normal T-cell expressed and secreted), a chemoattractant for memory T-cells, monocytes and eosinophils, has been shown to be highly expressed in mononuclear cells infiltrating the tracheal allograft [80]; the use of a neutralising anti-RANTES antibody decreases the number of CD4z infiltrating T-cells and prevents airway obliteration [81]. Similarly, monocyte chemoattractant protein (MCP)-1 acting through its receptor CCR2 is a potent chemoattractant for mononuclear cell.…”

“…Developing effective antifibroproliferative therapies (based on either novel immunosuppressive agents or cytokine/chemokine antagonists [81,84,120]) may well eventually be the best treatment option for bronchiolitis obliterans syndrome.…”