Macrophages contribute to cellular but not humoral mechanisms of acute rejection in rat renal allografts.
BACKGROUND
Cells of the monocyte/macrophage lineage have been implicated as effectors in acute allograft rejection based on short-term depletion studies. However, the therapeutic potential of targeting monocyte/macrophages in acute rejection is unknown. We investigated the potential of a c-fms kinase inhibitor (fms-I) in acute renal allograft rejection.


METHODS
Lewis rats underwent bilateral nephrectomy and received an orthotopic Dark Agouti renal allograft. Recipients received fms-I or vehicle from the time of transplantation until being killed on day 5.


RESULTS
Vehicle-treated rats developed severe allograft rejection with massive macrophage and T-cell infiltration. In contrast, fms-I substantially inhibited renal allograft dysfunction and structural damage with abrogation of macrophage and dendritic cell infiltration but had only a minor effect on the T-cell infiltrate. However, fms-I suppressed T-cell activation within the allograft, whereas systemic T- and B-cell activation was not affected. In a longer-term study to assess therapeutic potential, fms-I-treated rats developed severe antibody-mediated rejection on day 8 after transplantation. These transplants exhibited features of antibody-mediated rejection including capillaritis with thrombosis, acute tubular injury, IgG and C4d deposition, and neutrophil infiltration and activation. Interestingly, T-cell activation within these rejecting allografts remained suppressed, indicating separation of T-cell and antibody-mediated rejection.


CONCLUSIONS
This study demonstrates the ability of c-fms kinase blockade to selectively deplete monocyte/macrophages in acute allograft rejection, although this did not result in significant prolongation of allograft survival. Furthermore, we identify contrasting roles for macrophages in cellular and humoral mechanisms of acute renal allograft rejection.
1 Department of Nephrology, Monash Medical Centre, Clayton, Victoria, Australia. 2 Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia. 3 Address correspondence to: David J. Nikolic-Paterson, Department of Nephrology, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia.
Frank Y
FY
Ma
Naomi
N
Woodman
William R
WR
Mulley
John
J
Kanellis
David J
DJ
Nikolic-Paterson
D000208:Acute Disease; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000201:enzymology / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D006085:Graft Survival; D007111:Immunity, Cellular / Q000187:drug effects; D056724:Immunity, Humoral / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016030:Kidney Transplantation / Q000009:adverse effects*; D008213:Lymphocyte Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013997:Time Factors
D007166:Immunosuppressive Agents; D047428:Protein Kinase Inhibitors; D016186:Receptor, Macrophage Colony-Stimulating Factor