Neuroendocrine-Immune Modulation May Be Useful for Allograft-Specific Immunosuppression in Small Bowel Transplantation

doi:10.1016/j.transproceed.2006.05.012

Transplantation Proceedings

Volume 38, Issue 6, July–August 2006, Pages 1825-1826

https://doi.org/10.1016/j.transproceed.2006.05.012 Get rights and content

Abstract

Purpose

The authors have previously demonstrated that the neuropeptide bombesin (BBS) prevented allograft mucosal atrophy under tacrolimus (TRL) immunosuppression for rats small bowel transplantation (SBT). The present study investigated whether BBS had immunosuppressive effects on small bowel allografts.

Methods

Allogeneic SBT was performed heterotopically in rats (n = 12) that received daily administration of 0.1 mg/kg/d TRL from postoperative day 0 to day 14. Rats divided into two groups of six rats each were administered BBS or normal saline as a control. Biopsy of the allograft was performed from the stomal site on postoperative days 6, 10, and 14. The state of the graft mucosal villi was evaluated by H & E staining and TUNEL immunohistochemistry.

Results

By postoperative day 14, extensive mucosal destruction accompanied by heavy transmural cellular infiltration had developed in the control group. Lymphocytes and plasma cells infiltrated the lamina propria of the allograft without the distorting villous architecture in the BBS group. The TUNEL index of graft mucosa in the control group was 1.26% ± 0.37% (mean ± SD) and that in the BBS group, 0.59% ± 0.20%, respectively (p < .001).

Conclusion

This study demonstrated an immunosuppressive effect of bombesin on transplanted allografts, which might dramatically reduce the dose of TRL required for postoperative immunosuppression.

Section snippets

Methods

Allogeneic small bowel transplantation (SBTx) was performed heterotopically in rats (n = 12), using Brown Norway as donors and Lewis as recipients. The vascular anastomosis was performed using a cuff technique.2, 3 Both ends of the intestinal grafts were exteriorized as stomas, so-called Thiry-Vella fistula. From the first postoperative day, all rats were administered TRL at a dose of 0.1 mg/kg/d subcutaneously. The animals were divided into two groups of six rats each to be administered BBS

Results

On day 6, mononuclear cells began to infiltrate the lamina propria with mild distortion of the villous architecture in both groups. On day 10, cellular infiltration intensified in the mucosa and submucosa. Crypt damage was diffusely distributed and villous architecture was remarkably distorted in the control group. In the BBS group, however, villous architecture was well maintained with little crypt damage while cellular infiltration in the lamina propria layer was similar to that on

Discussion

The present study demonstrated that the neuropeptide BBS displayed an immunosuppressive effect on transplanted small bowel allografts with extremely low doses of TRL. To date, several immunosuppressive regimens had been reported to control acute rejection.1, 4, 5 There is no regimen that has no suppressive effect on systemic immunity. However, BBS has been reported to enhance systemic immunity.6, 7 Therefore, we speculate that coadministration of BBS with an extremely low dose of TRL would be

References (7)

T. Furukawa et al.
Small bowel allografts maintained by administration of bombesin while under immunosuppression
J Pediatr Surg
(2003)
S.P. Montgomery et al.
Efficacy and toxicity of a protocol using sirolimus, tacrolimus and daclizumab in a nonhuman primate renal allotransplant model
Am J Transplant
(2002)
G.J. Monchik et al.
Transplantation of small bowel in the rattechnical and immunological considerations
Surgery
(1971)

There are more references available in the full text version of this article.

Cited by (6)

Prenatal administration of neuropeptide bombesin promotes lung development in a rat model of nitrofen-induced congenital diaphragmatic hernia
2014, Journal of Pediatric Surgery
Citation Excerpt :
Our results showed BBS was considered to have promoted fetal lung maturity. As described previously, we investigated the effects of the BBS and elucidated its multipotent ability to maintain and modulate the mucosal structure and immunity of the gastrointestinal system [6–10]. Based on present and previous data, we speculate that BBS plays an important role via the same pathways in the respiratory and intestinal mucosa systems.
Fetal medical treatment to improve lung hypoplasia in congenital diaphragmatic hernia (CDH) has yet to be established. The neuropeptide bombesin (BBS) might play an important role in lung development. The present study aims to determine whether prenatally administered BBS could be useful to promote fetal lung development in a rat model of nitrofen-induced CDH.
Pregnant rats were administered with nitrofen (100 mg) on gestation day 9.5 (E9.5). BBS (50 mg/kg/day) was then daily infused intraperitoneally from E14, and fetal lungs were harvested on E21. The expression of PCNA was assessed by both immunohistochemical staining and RT-PCR to determine the amount of cell proliferation. Lung maturity was assessed as the expression of TTF-1, a marker of alveolar epithelial cell type II.
The lung-body-weight ratio was significantly increased in CDH/BBS(+) compared with CDH/BBS(−) (p < 0.05). The number of cells stained positive for PCNA and TTF-1 was significantly decreased in CDH/BBS(+) compared with CDH/BBS(−) (p < 0.01). The TTF-1 mRNA expression levels were significantly decreased in CDH/BBS(+) compared with CDH/BBS(−) (p < 0.05).
Prenatally administered BBS promotes lung development in a rat model of nitrofen-induced CDH. Neuropeptide BBS could help to rescue lung hypoplasia in fetal CDH.
Bombesin can minimize impairments of interstitial cells of Cajal induced by FK506 in small bowel transplantation
2009, Journal of Pediatric Surgery
Citation Excerpt :
Its actions in the intestine involve the regulation of gut motility, the modulation of gastrointestinal enteropancreatic hormone release, and the stimulation of intestinal epithelial growth. Previously, we reported that BBS also had a trophic effect on the reconstruction of allograft mucosa by stimulating the proliferation of mucosal crypt cells [7], an immunosuppressing effect against acute rejection [8], and a suppressing effect against ischemic reperfusion (I/R) injury in SBTx [9]. In addition, we reported that BBS could preserve graft enteric ganglia against FK506 neurotoxicity [10].
Interstitial cells of Cajal (ICC) are known as intestinal pacemaker cells and express c-kit on their membrane. Previously, we reported that FK506 had neurotoxicity to enteric ganglia, and bombesin (BBS) preserved them against FK506. The aim of this study was to investigate whether ICC was impaired by FK506 and whether ICC was preserved by BBS against FK506.
Twelve rats underwent allogeneic SBTx heterotopically and were divided into 2 groups as follows: group A underwent SBTx with FK506 and group B with FK506/BBS. All rats were administered FK506 daily. Either BBS or normal saline was infused continuously from day 14 to 28. Analysis of ICC was performed immunohistochemically with c-kit. Interstitial cells of Cajal were evaluated by counting the number of c-kit–positive clusters in each graft.
The expression of c-kit accumulated around 60% of PGP9.5-positive enteric ganglia. The number of c-kit–positive clusters in group A was 22.3 ± 5.5 clusters per cross section (C/CS) and that in group B was 36.3 ± 5.1 C/CS. Interstitial cells of Cajal were well preserved in group B. There was a significant difference between groups A and B (P <.001).
Interstitial cells of Cajal were impaired by FK506 in allografts, and BBS could minimize the impairment of ICC against FK506.
Reply
2007, Journal of Pediatric Surgery
Current understanding of alloimmunity of the intestinal graft
2015, Current Opinion in Organ Transplantation
International union of pharmacology. LXVIII. Mammalian bombesin receptors: Nomenclature, distribution, pharmacology, signaling, and functions in normal and disease states
2008, Pharmacological Reviews
Bombesin-related peptides and their receptors: Recent advances in their role in physiology and disease states
2008, Current Opinion in Endocrinology, Diabetes and Obesity

: This work was supported by grants-in-aid for scientific research from the Ministry of Education, Science and Culture of Japan (no. 16659482).

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Experimental modelImmunosuppressionNeuroendocrine-Immune Modulation May Be Useful for Allograft-Specific Immunosuppression in Small Bowel Transplantation

Abstract

Purpose

Methods

Results

Conclusion

Section snippets

Methods

Results

Discussion

J Pediatr Surg

Am J Transplant

Transplantation of small bowel in the rattechnical and immunological considerations

Surgery

Experimental model
Immunosuppression
Neuroendocrine-Immune Modulation May Be Useful for Allograft-Specific Immunosuppression in Small Bowel Transplantation