2013 - ISBTS 2013 Symposium

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Posters and Exhibition

15.94 - Loss of mucosal antimicrobial peptide expression during acute rejection after experimental allogenic intestinal transplantation can be reversed by anti-rejection treatment

Presenter: Martin, von Websky, , Germany
Authors: Martin von Websky¹, Simon Jaeger², Koji Kitamura¹, Thomas Pech¹, Kareem Abu-Elmagd³, Joerg Kalff¹, Jan Wehkamp², Nico Schaefer¹

Loss of mucosal antimicrobial peptide expression during acute rejection after experimental allogenic intestinal transplantation can be reversed by anti-rejection treatment

Martin von Websky¹, Simon Jaeger², Koji Kitamura¹, Thomas Pech¹, Kareem Abu-Elmagd³, Joerg Kalff¹, Jan Wehkamp², Nico Schaefer¹

¹Visceral Surgery, University Hospital of Bonn, Bonn, Germany; ²Clinical Pharmacology, Dr. Margarethe-Fischer-Bosch Institute, Stuttgart, Germany; ³Transplant Center, Cleveland Clinic, Cleveland, OH, United States

Background:

In intestinal transplantation (ITX), episodes of acute rejection (ACR) are frequent and often associated with severe systemic inflammatory response and sepsis. Bacterial overgrowth and subsequent translocation of microorganisms through the mucosal barrier could be facilitated due to reduced expression of mucosal antimicrobial peptides (AMPs) in ACR. Effective immunosuppression was hypothesized to reverse the loss of mucosal AMPs in intestinal allografts.

Methods:

To analyze the impact of ACR and immunosuppressive treatment on the expression of mucosal AMPs in intestinal grafts, allogenic ITX (BN to Lewis rats)was performed with different treatment regimens(no immunosuppression/continuous Tacrolimus/Tacrolimus rescue treatment). Isogenic ITX (Lewis to Lewis) served as control and native mucosa sampling was performed to determine baseline AMP expression. Graft mucosa was sampled at 4 and 7 d posttransplant for qPCR analysis of mucosal AMPs. Histologic ACR-grading was performed by two independent reviewers, using the Wu-rejection score on HE-stained graft sections.

Results:

Histology at 7d posttransplant displayed ACR in allogenic grafts without immunosuppression, ACR prevention by continuous Tacrolimus, ACR reversal by Tacrolimus-rescue treatment and residual inflammatory changes in isogenic grafts. In qPCR expression analysis of graft mucosa normalized to ß-Actin, Cryptdin 5, Cryptdin 7 and NP 3 were significantly reduced in allogenic graft mucosa versus isogenic graft mucosa (Cryptdin5: 17x; Cryptdin7: 11x; NP3: 14x reduction, respectively). Compared to native mucosa, the Cryptdins 5+7, NP3 and lysozym were likewise significantly reduced in allogenic, but not in isogenic, graft mucosa after ITX. Tacrolimus treatment (both continuous and rescue treatment) was able to prevent and/or reverse loss of AMP expression as ACR resolved.

Conclusion:

The expression of several important antimicrobial peptides (Cryptdins, Lysozym, NP3) was significantly reduced in ACR after allogenic ITX. Isogenic intestinal transplantation alone failed to negatively affect the expression of these antimicrobial peptides. Thus, the impairment of mucosal barrier function is mainly related to immune processes associated with ACR and may be countered by effective immunosuppression.

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