Perioperative infliximab application ameliorates acute rejection associated inflammation after intestinal transplantation.
As we have shown in the past, acute rejection-related TNF-α upregulation in resident macrophages in the tunica muscularis after small bowel transplantation (SBTx) results in local amplification of inflammation, decisively contributing to graft dysmotility. Therefore, the aim of this study is to investigate the effectiveness of the chimeric-monoclonal-anti-TNF-α antibody infliximab as perioperative single shot treatment addressing inflammatory processes during acute rejection early after transplantation. Orthotopic, isogenic and allogenic SBTx was performed in rats (BN-Lewis/BN-BN) with infliximab treatment. Vehicle and IV-immunoglobulin-treated animals served as controls. Animals were sacrificed after 24 and 168 h. Leukocyte infiltration was investigated in muscularis whole mounts by immunohistochemistry, mediator mRNA expression by Real-Time-RT-PCR, apoptosis by TUNEL and smooth muscle contractility in a standard organ bath. Both, infliximab and Sandoglobulin® revealed antiinflammatory effects. Infliximab resulted in significantly less leukocyte infiltration compared to allogenic controls and IV-immunoglobulin, which was accompanied by lower gene expression of MCP-1 (24 h), IFN-γ (168 h) and infiltration of CD8-positive cells. Smooth muscle contractility improved significantly after 24 h compared to all controls in infliximab treated animals accompanied by lower iNOS expression. Perioperative treatment with infliximab is a possible pharmaceutical approach to overcome graft dysmotility early after SBTx.
Pech
T
T
Department of Surgery, Rheinische Friedrich-Wilhelms-Universität Bonn, Germany Division of Intestinal Transplantation, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, PA, USA.
Finger
T
T
Fujishiro
J
J
Praktiknjo
M
M
Ohsawa
I
I
Abu-Elmagd
K
K
Limmer
A
A
Hirner
A
A
Kalff
J C
JC
Schaefer
N
N
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D017209:Apoptosis; D018723:Bethanechol / Q000494:pharmacology; D005769:Gastrointestinal Motility; D006084:Graft Rejection / Q000517:prevention & control*; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use; D007249:Inflammation / Q000517:prevention & control*; D000069285:Infliximab; D016753:Interleukin-10 / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000096:biosynthesis; D007421:Intestine, Small / Q000637:transplantation*; D020556:Neutrophil Infiltration; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D019990:Perioperative Care; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D014184:Transplantation, Homologous / Q000276:immunology; D014185:Transplantation, Isogeneic / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology
D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D016756:Immunoglobulins, Intravenous; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D018723:Bethanechol; D016753:Interleukin-10; D000069285:Infliximab; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat