Donor T-cell production of RANTES significantly contributes to the development of idiopathic pneumonia syndrome after allogeneic stem cell transplantation.
Idiopathic pneumonia syndrome (IPS) is a major cause of mortality following allogeneic stem cell transplantation (allo-SCT). Clinical and experimental data support a role for conditioning-induced inflammation and alloreactive T-cell responses in IPS pathophysiology, but the mechanisms by which donor leukocytes are ultimately recruited to the lung are not fully understood. RANTES is a chemokine ligand that is up-regulated during inflammation and promotes the recruitment of T cells and macrophages to sites of tissue damage. Using a lethally irradiated murine SCT model (B6 --> B6D2F1), we evaluated the role of donor leukocyte-derived RANTES in the development of IPS. Pulmonary mRNA and protein levels of RANTES were significantly elevated in allo-SCT recipients compared to syngeneic controls and were associated with enhanced mRNA expression of CCR5 and CCR1 and with inflammatory cell infiltration into the lung. Allo-SCT with RANTES-/- donor cells significantly decreased IPS and improved survival. Combinations of allogeneic wild-type or RANTES-/- bone marrow with wild-type or RANTES-/- T cells demonstrated that the expression of RANTES by donor T cells was critical to the development of lung injury after SCT. These data reveal that donor T cells can help regulate leukocyte recruitment to the lung after allo-SCT and provide a possible mechanism through which inflammation engendered by SCT conditioning regimens is linked to allo-specific T-cell responses during the development of IPS.
Hildebrandt
Gerhard C
GC
Department of Pediatrics, Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI, USA.
Olkiewicz
Krystyna M
KM
Choi
Sung
S
Corrion
Leigh A
LA
Clouthier
Shawn G
SG
Liu
Chen
C
Serody
Jonathan S
JS
Cooke
Kenneth R
KR
D000818:Animals; D001853:Bone Marrow / Q000276:immunology / Q000473:pathology; D016026:Bone Marrow Transplantation / Q000401:mortality; D018946:Chemokine CCL5 / Q000172:deficiency / Q000276:immunology*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000473:pathology; D055370:Lung Injury; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011014:Pneumonia / Q000209:etiology / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D054389:Receptors, CCR1; D019713:Receptors, CCR5 / Q000276:immunology; D019707:Receptors, Chemokine / Q000276:immunology; D013577:Syndrome; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D015854:Up-Regulation / Q000276:immunology
C515300:CCR1 protein, human; C515301:Ccr1 protein, mouse; D018946:Chemokine CCL5; D054389:Receptors, CCR1; D019713:Receptors, CCR5; D019707:Receptors, Chemokine