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The immunosuppressive effect of rapamycin on mouse small bowel transplantation
1Laboratories of Experimental Surgery and Transplantation Immunology, Research Center, Notre-Dame Hospital, University of Montreal, Canada.
Abstract:
The efficacy of rapamycin (RAPA) was tested on small bowel transplantation in the mouse and compared with cyclosporine (CsA). Four groups were involved, each one included three combinations (n > or = 6) for evaluation of host-versus-graft (HVG, C57BL/6 X BALB/c F1 (CB6F1)-to-BALB/c), graft-versus-host (GVH, BALB/c-to-CB6F1), and combined HVG and GVH responses (C57BL/6-to-BALB/c). Grafts were transplanted to recipients heterotopically. Groups were as follows: group 1: naive controls; groups 2 and 3: recipient mice treated with RAPA 2 mg/kg/day and 4 mg/kg/day orally for 14 days, respectively; group 4: recipient mouse treated with CsA 4 mg/kg/day orally for 14 days. In the HVG model, the mean survival time (MST) of recipients was significantly longer in group 2 (32.9 +/- 17.7 days, P=0.006), group 3 (32.7 +/- 10.4 days, P=0.0001), and group 4 (37.9 +/- 11.8 days, P=0.0001), compared with naive controls in group 1 (8.5 +/- 1.6 days). In the GHV model, the MST of recipients in group 2 (41.8 +/- 19.9 days, P=0.002), group 3 (48.2 +/- 21.4 days, P=0.001) and group 4 (56.5 +/- 30.6 days, P=0.003) were significantly prolonged compared with control group 1 (8.5 +/- 1.6 days). In combined HVG and GVH responses, MST of recipient in group 2 (20.9 +/- 4.9 days, P=0.0001), group 3 (27.0 +/- 4.3 days, P=0.008), and group 4 (35.2 +/- 23.9 days, P=0.0001) were also significantly longer than that in controls (6.9 +/- 1.4 days), but in all three combinations, there were no statistically significant differences between groups 2 and 3, groups 2 and 4, or groups 3 and 4 (P>0.05). RAPA is a potent immunosuppressant able to significantly prolong small bowel allograft survival in mice using a short-term treatment. There is no statistically significant difference in recipient survival between low and high doses of RAPA treatment and the CsA standard dose used in this study.
Insights
Rapamycin (RAPA) significantly prolongs small bowel allograft survival in mice, demonstrating potent immunosuppressive effects comparable to cyclosporine (CsA). Short-term RAPA treatment showed no significant difference between low and high doses in improving recipient survival.
Area of Science:
- Transplantation immunology
- Immunopharmacology
Background:
- Small bowel transplantation is a complex procedure with significant risks of rejection.
- Effective immunosuppression is crucial for allograft survival.
- Rapamycin (RAPA) and cyclosporine (CsA) are commonly used immunosuppressants.
Purpose of the Study:
- To evaluate the efficacy of rapamycin (RAPA) in small bowel transplantation in a mouse model.
- To compare the immunosuppressive effects of RAPA with cyclosporine (CsA).
Main Methods:
- A mouse model of small bowel transplantation was used, evaluating host-versus-graft (HVG), graft-versus-host (GVH), and combined responses.
- Recipients were treated with two different doses of RAPA (2 mg/kg/day and 4 mg/kg/day) or CsA (4 mg/kg/day) orally for 14 days.
- Mean survival time (MST) was used as the primary endpoint.
Main Results:
- Both RAPA and CsA significantly prolonged MST in all tested models (HVG, GVH, and combined) compared to naive controls.
- No statistically significant differences in MST were observed between the low and high doses of RAPA, or between RAPA and CsA treatments across all models.
- Short-term treatment with RAPA demonstrated potent immunosuppressive capabilities.
Conclusions:
- Rapamycin is a potent immunosuppressant that significantly enhances small bowel allograft survival in mice.
- Short-term RAPA treatment is effective and comparable to CsA, with no significant dose-dependent differences observed.
- These findings support the potential of RAPA as an effective immunosuppressive agent in small bowel transplantation.