Intestinal Regeneration, Residual Function and Immunological Priming Following Rescue Therapy After Rat Small Bowel Transplantation

Abstract

Clinical evidence suggests that recurrent acute cellular rejection (ACR) may trigger chronic rejection and impair outcome after intestinal transplantation. To test this hypothesis and clarify underlying molecular mechanisms, orthotopic/allogenic intestinal transplantation was performed in rats. ACR was allowed to occur in a MHC-disparate combination (BN-LEW) and two rescue strategies (FK506monotherapy vs. FK506+infliximab) were tested against continuous immunosuppression without ACR, with observation for 7/14 and 21 days after transplantation. Both, FK506 and FK506+infliximab rescue therapy reversed ACR and resulted in improved histology and less cellular infiltration. Proinflammatory cytokines and chemotactic mediators in the muscle layer were significantly reduced in FK506 treated groups. Increased levels of CD4, FOXP3 and IL-17 (mRNA) were observed with infliximab. Contractile function improved significantly after FK506 rescue therapy, with a slight benefit from additional infliximab, but did not reach nontransplanted controls. Fibrosis onset was detected in both rescue groups by Sirius-Red staining with concomitant increase of the fibrogenic mediator VEGF. Recovery from ACR could be attained by both rescue therapy regimens, progressing steadily after initiation of immunosuppression. Reversal of ACR, however, resulted in early stage graft fibrosis. Additional infliximab treatment may enhance physiological recovery of the muscle layer and enteric nervous system independent of inflammatory reactions.

Short-Term TNF-Alpha Inhibition Reduces Short-Term and Long-Term Inflammatory Changes Post-Ischemia/Reperfusion in Rat Intestinal Transplantation

“…The effect of TNF>-induced molecular changes during ischemia/ reperfusion injury (IRI) on the induction of permanent changes is currently being discussed (10).…”

Difficulties, guidelines and review of developing an acute rejection model after rat intestinal transplantation

“…We used the same score (0-3) to determine rejection [24]. First, Pech et al studied the effects of the immunosuppressive agents when AR appeared; they then studied the specific combination of TAC and infliximab to reduce the inflammatory response and dysmotility; finally, they studied the regeneration, residual function and immunological status after treating rejection [8,9,13]. We initially attempted to reproduce the Pech model in our experiments.…”

“…We initially used Wistar rats as recipients based on previous publications from our center (not directly related to rejection) [17,[19][20][21]. Because we did not find signs of rejection at the 6th day, we changed to Lewis rats, based on the previously described models [8,9,13,73,74], and given the fully allogenic BN-to-Lewis combination appears to be histoincompatible and rejection has been described as the dominant immunologic response either without or with immunosuppression [56,75]. BN rats have been reported to have "universal donor" qualities for unknown reasons.…”

“…For these reasons, it is difficult to compare the various publications and to establish conclusions before starting as a novice in the field [4][5][6][8][9][10][11][12][13][14][15][16][17][18].…”

Gut Permeability and Glucose Absorption Are Affected at Early Stages of Graft Rejection in a Small Bowel Transplant Rat Model

“…2 By far, rat ITx models has been the most extensively used mainly as consequence of technical aspects and the availability of different strains. 3 Since the standardization of procedures in the last decade of the XXth.…”