Anti-LFA-1 antibody postpones T-cell receptor triggering while preserving generation of regulatory T cells in T-cell receptor anti-HY transgenic mice.

BACKGROUND: Anti-LFA-1 (CD11a) antibody increases allograft survival and/or induces tolerance in murine models, but its mechanisms of action remain to be elucidated. METHODS: Rag-2-/- H-2b recipient mice, bearing a transgenic T-cell receptor specific for the male antigen HY presented by MHC class II molecule, were transplanted with a C57BL/6 (H-2b) male heart with or without administration of anti-LFA-1 antibody from days -1 to 9. RESULTS: Treatment prevented the transient episode of acute graft rejection observed in nontreated mice and maintained a naive phenotype and proliferative characteristics comparable to that of naive transgenic lymphocytes on day 7 during treatment, with decreased IFN-gamma mRNA and increased IL-4 mRNA. On day 14, phenotype and proliferative response of lymphocytes in treated mice was comparable to those of untreated animals. Furthermore, treatment did not interfere with the generation of CD4+Vbeta6+CD25+ (Foxp3) cells that were observed in long-term nontreated tolerant mice. CONCLUSIONS: This in vivo model demonstrates that anti-LFA-1 treatment induced a transient blockade of antigen recognition, which inhibited and postponed induction of signal 1 via the TCR and decreased the intensity of the Th1 response. Importantly, LFA-1 blockade did not disturb spontaneous generation of regulatory mechanism. This treatment would be compatible in clinical settings with other therapeutics inducing regulatory mechanisms.

Enhanced in situ expression of NF-kappaBp65 is an early marker of intestinal graft rejection in rats.

BACKGROUND: Although intestinal transplantation provides a unique situation of free access to the graft because of the presence of temporary enterostomas, evaluation of local immunosuppression is still an unresolved issue and may constitute one of the causes of grafting failure. AIMS: To study in a rat model of allogeneic intestinal transplantation the expression of transcription factors involved in lymphocyte activation in situ in the graft and to identify factors reflecting the efficiency of drug immunosuppression. METHODS: Intestinal transplantation was performed in a Brown Norway (RT1n-donors)-Lewis (RT1(l)-recipients) rat strain combination. The animals were treated with tacrolimus to induce tolerance or left untreated. Syngeneic intestinal grafts and intestine from donor rats with peritonitis were used as controls. NF-kappaBp65, p-c-Jun, interleukin 2 receptor (CD25), and major histocompatibility complex class II antigen (OX-6) expression was studied in graft biopsies on days 2 and 5 by immunohistochemistry. RESULTS: On day 2, before the onset of histologic signs of rejection, the number of cells expressing NF-kappaBp65 in the pericryptic lamina propria was significantly higher in untreated recipients of allogeneic grafts than in the other groups (P = .009). NF-kappaBp65 expression then fell between days 2 and 5 (P = .009). Classic markers of T-cell activation (CD25 and OX-6) were expressed during rejection in the lamina propria and on crypt enterocytes, respectively. p-c-Jun expression did not differ among the 3 groups. CONCLUSION: NF-kappaBp65 expression in intestinal grafts is a precocious sign of local activation during rejection and could thus serve to optimize the management of immunosuppressive therapy.

Small bowel allografts maintained by administration of bombesin while under immunosuppression.

BACKGROUND/PURPOSE: The aim of this study was to determine if Bombesin (BBS) could help maintain the mucosal villus state in small bowel allografts without inducing acute rejection under immunosuppression. METHODS: Allogeneic small bowel transplantation was performed heterotopically in rats (n = 12). All rats received daily administration of FK506 from postoperative day 0 to day 28. On postoperative day 14, rats were divided into 2 groups of 6 rats each, and administered BBS or normal saline as a control. After 2 weeks of treatment, the rats were killed, and the graft mucosal villus state was evaluated by H&E staining, and crypt cell proliferation analysis was performed using immunohistochemistry with proliferative cell nuclear antigen (PCNA). RESULTS: Villi were thin, and villus blunting was marked in the control group. The BBS group showed that the villi of the grafts were well maintained, and the volume of the lamina propria mucosa was adequately preserved. The PCNA labeling index of crypt cells in the control group was 40.06 +/- 3.36 (mean +/- SD) and that in the BBS group was 61.02 +/- 4.27. There was a significant difference (P <.001) between the 2 groups. CONCLUSIONS: BBS maintained allograft epithelial cells and the volume of the lamina propria intestinal mucosa, stimulating proliferation of crypt cells under immunosuppression without inducing acute rejection.

Proximal jejunostomy with or without myectomy-myotomy modification in five infants with total intestinal aganglionosis: An experience with surgical treatments in a single institution.

BACKGROUND: Total intestinal aganglionosis is characterized by the absence of intramural ganglion cells, in which the disease's involvement extends from the stomach to the anorectum. This disease was suggested previously to be incompatible with life, but recently an extended small bowel myectomy-myotomy has achieved some prolonged survivors. METHODS: Five patients with total intestinal aganglionosis underwent laparotomy at 1 to 5 days of age. Surgery was performed as a simple jejunostomy 60 to 70 cm below the ligament of Treitz in the initial 2, jejunustomy 30 cm below the ligament of Treitz in 1, and jejunostomy with myectomy-myotomy modification 30 to 35 cm below the ligament of Treitz in the remaining 2 infants. RESULTS: The initial 2 patients died of sepsis, possibly derived from frequent enteritis and bacterial translocation at 7 and 8 months of age. Another patient had prolonged survival but died of hepatic failure at 1 year, 4 months. The remaining 2 children have survived beyond 2 years of age without any liver dysfunction, receiving a combination of enteral and parenteral nutrition. CONCLUSIONS: The more proximal site (30 to 35 cm below the ligament of Treitz) of jejunostomy with myectomy-myotomy modification appeared to be preferable for prolonged survival in these 5 patients with total intestinal aganglionosis.