Acceleration of idiopathic pneumonia syndrome (IPS) in the absence of donor MIP-1 alpha (CCL3) after allogeneic BMT in mice.
Idiopathic pneumonia syndrome (IPS) is a significant cause of morbidity and mortality after bone marrow transplantation (BMT) in humans. We developed a murine IPS model in which lethal pre-BMT conditioning and allogeneic T cells results in the recruitment of host monocytes and then donor T cells into the lung by day 7 after BMT, concomitant with development of severe lung dysfunction. We reported the T cell-dependent production of the T cell-attracting chemokine macrophage inflammatory protein-1 alpha (MIP-1 alpha) in the lungs of such recipient mice. We reasoned that MIP-1 alpha might be a critical mediator of IPS. Lethally conditioned mice received transplants of major histocompatibility complex-disparate marrow and either wild-type (MIP-1 alpha(+/+)) or knockout (MIP-1 alpha(-/-)) spleen cells. Recipients of MIP-1 alpha(-/-) cells exhibited accelerated mortality and a decrease in specific compliance that appeared earlier than in recipients of MIP-1 alpha(+/+) cells. Donor CD4(+) and CD8(+) T cell expansion was increased in the spleens of recipients of MIP-1 alpha(-/-) cells. Lungs of recipients of MIP-1 alpha(-/-) cells had earlier recruitment of both T-cell subsets by day 3 after BMT, concomitant with the influx of cells expressing the cytolysins granzymes A and B. Monocyte recruitment was not altered. Levels of inflammatory cytokines were not increased and levels of T cell-attracting chemokines were decreased. The level of the anti-inflammatory cytokine interleukin 13 (IL-13) was lower in the serum and lungs of recipients of MIP-1 alpha(-/-) cells, indicating a skewing toward a more inflammatory T helper cell type 1 (Th1) cytokine milieu. Donor-derived MIP-1 alpha may play a role in allogeneic-induced IPS by limiting aggressive expansion of CD4(+) and CD8(+) T cells.
Panoskaltsis-Mortari
Angela
A
Department of Pediatrics, Division of Hematology-Oncology, Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, 55455, USA. panos001@umn.edu
Hermanson
John R
JR
Taras
Elizabeth
E
Wangensteen
O Douglas
OD
Serody
Jonathan S
JS
Blazar
Bruce R
BR
D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018925:Chemokines / Q000032:analysis; D002634:Chemotaxis, Leukocyte; D016207:Cytokines / Q000032:analysis; D006086:Graft vs Host Disease / Q000209:etiology / Q000473:pathology; D053804:Granzymes; D008168:Lung / Q000737:chemistry / Q000276:immunology / Q000503:physiopathology; D008170:Lung Compliance; D019402:Macrophage Inflammatory Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011014:Pneumonia / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D011828:Radiation Chimera; D012697:Serine Endopeptidases / Q000032:analysis; D018417:Th1 Cells / Q000276:immunology; D013997:Time Factors; D014184:Transplantation, Homologous / Q000009:adverse effects*
D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018925:Chemokines; D016207:Cytokines; D019402:Macrophage Inflammatory Proteins; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases