Post-BMT lung injury occurs independently of the expression of CCL2 or its receptor, CCR2, on host cells.
Idiopathic pneumonia syndrome (IPS) is a significant cause of mortality post-bone marrow transplant (BMT) in humans. In our murine model, lethal pre-BMT conditioning and allogeneic T cells result in the recruitment of host antigen-presenting cells (APC) and donor T cells into the lung post-BMT concomitant with development of severe lung dysfunction. CCL2 induction is found in bronchoalveolar lavage fluid (BALF) before host monocyte influx. The major receptor for CCL2 is CCR2 present on monocytes; this interaction can play a crucial role in monocyte recruitment in inflammation. To determine whether blockade of the CCL2/CCR2 pathway could hinder host monocyte influx, lethally conditioned wild-type (WT), CCL2(-/-), or CCR2(-/-) mice were transplanted with allogeneic marrow and spleen cells. WT and (-/-) recipients exhibited equivalent lung dysfunction post-BMT. The frequencies of host macrophages as well as donor CD4(+) and CD8(+) T cells in lungs post-BMT did not differ between WT and (-/-) recipients. However, the T cell dependency of the host CD11b(+) major histocompatibility complex class II(+) cell influx was lost in CCR2(-/-) recipients. In CCR2(-/-) mice, this influx was accompanied by elevated levels of CCL20. Post-BMT BALF and sera of (-/-) mice did not reveal any decrease in cytokines or chemokines compared with WT mice. CCL2(-/-) mice had a deficiency of CCL2 in their BALF and sera post-BMT, confirming our hypothesis that CCL2 is predominantly host derived. Therefore, IPS can occur independently of host expression of CCL2 or CCR2, and compensatory mechanisms exist for regulating APC recruitment into the lung during the early post-BMT period.
Panoskaltsis-Mortari
Angela
A
University of Minnesota, Department of Pediatrics, Division of Hematology-Oncology, 420 Delaware St. SE, Minneapolis, MN 55455, USA. panos001@umn.edu
Hermanson
John R
JR
Taras
Elizabeth
E
Wangensteen
O Douglas
OD
Charo
Israel F
IF
Rollins
Barrett J
BJ
Blazar
Bruce R
BR
D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects*; D018932:Chemokine CCL2 / Q000235:genetics*; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000276:immunology / Q000401:mortality / Q000503:physiopathology; D008285:Major Histocompatibility Complex / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009000:Monocytes / Q000276:immunology; D011014:Pneumonia / Q000276:immunology / Q000401:mortality / Q000503:physiopathology*; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000235:genetics*; D012720:Severity of Illness Index; D015996:Survival Rate
C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054390:Receptors, CCR2; D019707:Receptors, Chemokine