ABSTRACT
Graft rejection remains a formidable problem contributing to poor outcomes after lung transplantation. Blocking chemokine pathways have yielded promising results in some organ transplant systems. Previous clinical studies have demonstrated upregulation of CCR2 ligands following lung transplantation. Moreover, lung injury is attenuated in CCR2-deficient mice in several inflammatory models. In this study, we examined the role of CCR2 in monocyte recruitment and alloimmune responses in a mouse model of vascularized orthotopic lung transplantation. The CCR2 ligand MCP-1 is upregulated in serum and allografts following lung transplantation. CCR2 is critical for the mobilization of monocytes from the bone marrow into the bloodstream and for the accumulation of CD11c(+) cells within lung allografts. A portion of graft-infiltrating recipient CD11c(+) cells expresses both recipient and donor MHC molecules. Two-photon imaging demonstrates that recipient CD11c(+) cells are associated with recipient T cells within the graft. While recipient CCR2 deficiency does not prevent acute lung rejection and is associated with increased graft infiltration by T cells, it significantly reduces CD4(+) T(h)1 indirect and direct allorecognition. Thus, CCR2 may be a potential target to attenuate alloimmune responses after lung transplantation.
Subject(s)
Lung Transplantation/methods , Monocytes , Animals , Chemokines , Graft Rejection/immunology , Inflammation , Lymphocyte Count , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Monocytes/immunology , Monocytes/metabolism , Monocytes/physiology , Pneumonia/metabolism , T-Lymphocytes/metabolism , Transplantation, HomologousABSTRACT
Leukocyte recruitment is a key host defense mechanism to infection and a salient feature of autoimmune diseases such as arthritis. The cell dynamics of these processes are difficult to study due to the challenge of tracking cells flowing in the circulation and migrating through light scattering tissues. Here, we describe a noninvasive two-photon (2P) microscopy approach to study leukocyte homing in the mouse footpad. In the absence of inflammation, cells moved > several hundred microm/s in vessels and only rarely adhered to endothelium or entered the tissue parenchyma. In response to bacterial infection, neutrophils moved in small capillaries at reduced speeds of (14-45 microm/min) and rolled in larger vessels at 5-60 microm/min. Within minutes of adoptive transfer, neutrophils entered the connective tissue and crawled with a median velocity of 7.3 microm/min. 2P imaging has excellent spatiotemporal resolution and is a promising in vivo approach to study the cellular basis of inflammation.
Subject(s)
Foot/anatomy & histology , Leukocyte Rolling/physiology , Leukocytes/metabolism , Microscopy/methods , Adoptive Transfer , Animals , CD11c Antigen/genetics , CD11c Antigen/metabolism , Leukocytes/cytology , Luminescent Proteins/genetics , Luminescent Proteins/metabolism , Mice , Mice, Inbred C57BL , Mice, TransgenicABSTRACT
The induction of an adaptive immune response is an essential step in the generation of long-lasting, protective immunity to pathogens. Many studies over the last few decades have identified the cell populations involved in the generation of antigen-specific immunity and elucidated the role of many important molecules. However, because of the low precursor frequency of antigen-specific cells, the immune system must be highly dynamic, surveying most sites of the body. Recent studies have, therefore, begun to examine how the cells of the immune system interact in vivo during the induction of an immune response, identifying new and important roles for certain molecules and revealing how previously unrecognised alterations in cell-cell interactions can have significant implications for the resulting immune response. Here we review some of these recent studies that provide a valuable insight into the mechanisms involved in the induction of immunity.
