Infiltration patterns of macrophages and lymphocytes in chronically rejecting rat kidney allografts

The migration of circulating leukocytes to sites of inflammation or antigen is based, at least in part, on the activities of adhesion molecules. In the context of organ transplantation, some of these have been shown to be upregulated during acute allograft rejection. As their role during chronic rejection has not been examined, we have used an established rat model to compare sequentially the presence of host cells within the grafts, as defined immunohistologically, with patterns of in vitro leukocyte binding and their dependence upon particular adhesion molecules. Various donor populations of peripheral blood lymphocytes (PBL), lymph node lymphocytes (LNL), and splenic monocytes were interacted with snap-frozen sections of allografted, isografted, and native kidneys at serial intervals up to 24 weeks after transplantation. Monocyte binding in the allografts rose at 8 weeks and peaked at 12 weeks, a period preceding the maximum numbers of macrophages noted immunohistologically in the chronically rejecting grafts at 16 weeks. Lymphocyte binding and infiltration patterns were similar, remaining stable throughout the follow-up period and consistently greater than those noted in isografts. In vitro binding of the monocytes was inhibited by mAbs against ICAM-1, LFA-1, CD18, and MAC-1; MAC-1 did not influence lymphocyte binding, although the other mAbs were effective. We conclude that adhesion molecules are responsible, at least in part, for patterns of cell populations infiltrating chronically rejecting renal allografts.     

Pancreatic transplant imaging

Forty-four clinical episodes of suspected (pancreas) transplant rejection in 17 pancreatic transplantation patients were reviewed retrospectively. The clinical impression of acute graft rejection, chronic rejection, or nonrejection in each episode was correlated with the results of 19 nuclear medicine, 12 ultrasound (US), and 44 magnetic resonance (MR) imaging studies. US was found to be a moderately sensitive (82%) method of detecting graft rejection. US also was effective in identifying intra- and peripancreatic fluid accumulations. Nuclear medicine imaging was also a sensitive technique (86%) and the only modality that provided physiologic information regarding graft perfusion. MR imaging allowed correct prediction of the presence or absence of graft rejection in 39 of 44 cases (sensitivity, 100%; specificity, 76%) and was an effective means of detecting pathologic fluid collections. Nuclear medicine, US, and MR imaging are all believed to be sensitive methods of detecting graft rejection and are complementary adjuncts to the clinical evaluation of pancreatic transplants.     

Late mortality and morbidity in recipients of long-term renal allografts

The experience of the Peter Bent Brigham Hospital with 217 renal allografts functioning for more than 5 years is reviewed. Patient and graft survival were similar after 5 years, with patient survival being 88 and 66% at 10 and 15 years, respectively, and graft survival 85 and 75% at the same time intervals. Actuarial graft survival at 15 years was higher than patient survival because death with a functioning graft was not considered to be graft failure. No differences in patients or graft survival were found between living related and cadaver donor allografts. There were 33 deaths (15.2%), occurring from 5 1/2 to 20 1/2 years post-transplantation. Chronic liver failure and sepsis were the most common causes of death. Thirty-two patients (14.7%) lost their grafts after 5 years, most commonly from chronic rejection. Another 33 patients (15.2%) had evidence of graft dysfunction secondary to chronic rejection, recurrent glomerulonephritis, ureteral obstruction, or renal artery stenosis. Chronic rejection was generally not responsive to alterations in immunosuppressive medication. Complications of varying severity were common affecting 204 (94%) of the patients. The most frequent were hypertension, cataracts, avascular necrosis, malignancy, urinary tract infection, and pneumonia. These data demonstrate that transplant-related mortality and morbidity continue to occur in recipients of long-term renal allografts. These patients require careful and continuing care in medical centers experienced in transplantation.     

A Comparison of Adverse Events and Functional Outcomes After Restorative Proctocolectomy for Familial Adenomatous Polyposis and Ulcerative Colitis

Purpose Restorative proctocolectomy is the procedure of choice for patients undergoing proctocolectomy for familial adenomatous polyposis or ulcerative colitis. This meta-analysis was designed to identify differences in adverse events and functional outcomes between these two groups. Methods Studies published between 1986 and 2003 that compared outcomes between patients with familial adenomatous polyposis and ulcerative colitis were included. Meta-analytical techniques using random effect models were used to compare short-term and long-term adverse events as well as functional outcomes between the groups. Results Nineteen studies comprising 5,199 patients (familial adenomatous polyposis, 782; ulcerative colitis, 4,417) were analyzed. There were no significant differences in immediate postoperative adverse events between the two groups. Pouch-related fistulation was significantly increased in the ulcerative colitis group (10.5 percent vs. familial adenomatous polyposis 4.8 percent; odds ratio 2.31; P < 0.001). There was no significant difference in pouch failure between the two groups (ulcerative colitis 5.8 percent vs. familial adenomatous polyposis 4.5 percent; odds ratio 1.22; P = 0.43). The incidence of pouchitis was significantly greater in the ulcerative colitis group (30.1 vs. 5.5 percent; odds ratio 6.44; P < 0.001). Patients with familial adenomatous polyposis had a significant advantage in stool frequency with one less motion per 24 hours (95 percent confidence interval, 0.21–1.76; P = 0.01). Conclusions In contrast to studies reporting similar outcomes for patients undergoing restorative proctocolectomy for familial adenomatous polyposis or ulcerative colitis, the present meta-analysis suggested that patients with ulcerative colitis are at greater risk of pouch-related fistulation and pouchitis. Although there was an increase in the 24-hour stool frequency in the ulcerative colitis group, this may be accounted for by the younger age at surgery in the familial adenomatous polyposis group. Henry S. Tilney is sponsored by a research grant from The Royal College of Surgeons of England. Read at the meeting of the Association of Surgeons of Great Britain and Ireland, Edinburgh, Scotland, May 3 to 5, 2006.     

Lactobacillus rhamnosus CNCM I-3690 and the commensal bacterium Faecalibacterium prausnitzii A2-165 exhibit similar protective effects to induced barrier hyper-permeability in mice

Impaired gut barrier function has been reported in a wide range of diseases and syndromes and in some functional gastrointestinal disorders. In addition, there is increasing evidence that suggests the gut microbiota tightly regulates gut barrier function and recent studies demonstrate that probiotic bacteria can enhance barrier integrity. Here, we aimed to investigate the effects of Lactobacillus rhamnosus CNCM I-3690 on intestinal barrier function. In vitro results using a Caco-2 monolayer cells stimulated with TNF-α confirmed the anti-inflammatory nature of the strain CNCM I-3690 and pointed out a putative role for the protection of the epithelial function. Next, we tested the protective effects of L. rhamnosus CNCM I-3690 in a mouse model of increased colonic permeability. Most importantly, we compared its performance to that of the well-known beneficial human commensal bacterium Faecalibacterium prauznitzii A2-165. Increased colonic permeability was normalized by both strains to a similar degree. Modulation of apical tight junction proteins expression was then analyzed to decipher the mechanism underlying this effect. We showed that CNCM I-3690 partially restored the function of the intestinal barrier and increased the levels of tight junction proteins Occludin and E-cadherin. The results indicate L. rhamnosus CNCM I-3690 is as effective as the commensal anti-inflammatory bacterium F. prausnitzii to treat functional barrier abnormalities.     

Prospective comparative trial of autologous versus allogeneic bone marrow transplantation in patients with non-Hodgkin's lymphoma

A prospective comparative trial of allogeneic versus autologous bone marrow transplant (BMT) was conducted. Sixty-six consecutive patients (median age, 41; range, 15 to 60; female:male ratio = 21:45) entered this clinical trial. Priority for allogeneic BMT was given to patients who were 55 or younger and had a major histocompatibility complex- matched or 1-antigen-disparate sibling donor. Autologous BMT was offered to all other patients whose age was 60 or younger. Patients who had no sibling donor and who had BM involvement at the time of evaluation were not eligible. Thirty-one patients received an allograft, and 35 patients received an autograft. Thirteen patients received a BM graft purged with 4-hydroperoxycyclophosphamide because of previous BM involvement. Patients who had previous radiation to the thoracic and/or abdominal areas of more than 20 Gy received a preparative regimen consisting of cyclophosphamide (1,800 mg/m2/d for 4 days), VP-16 (200 mg/m2 every 12 hours for 8 doses), and 1,3-bis(2- chloroethyl)-1-nitrosourea (600 mg/m2 as 1 dose). Other patients received cyclophosphamide 1,800 mg/m2/d for 4 days followed by total body irradiation of 12 Gy administered as a single daily fraction over 4 days. With a median follow-up of 14 months, the progression-free survival (PFS) for autograft and allograft recipients was 24% +/- 8% (+/- SE) and 47% +/- 9%, respectively, (P = .21). However, the probability of disease progression was significantly higher in the autologous group (69% +/- 9%) than in the allogeneic group (20% +/- 10%; P = .001). When other confounding prognostic factors were adjusted in the multivariate analysis, chemosensitive disease and allograft were found to have a significant favorable influence on probability of disease progression (P = .03 and .003), but only chemosensitive disease had a significant influence on the PFS (P < .002). Our results suggest the existence of graft-versus-lymphoma effect and also support the rationale of using immunotherapy after autologous BMT. Allogeneic BMT should be preferable to autologous BMT in younger patients with lymphoma.