Thomas K. Lee

Pathogenesis of pancreatic sepsis

Although pancreatic sepsis is the most common cause of major morbidity and mortality associated with acute pancreatitis, the pathogenesis of such infections is unknown. Since intraperitoneal foci of inflammation are known to promote bacterial translocation, we hypothesized that acute pancreatitis promotes bacterial translocation that leads to infection of the inflamed pancreas and peripancreatic tissues. Non-lethal acute pancreatitis was induced in rats, and the translocation of live bacteria to the pancreas, mesenteric lymph nodes, liver, and spleen was determined. The presence of orally fed fluorescent beads, sensitive inert markers of translocation, was also determined in the pancreas and mesenteric lymph nodes. Live bacteria were recovered from 33% of the pancreata of rats with acute pancreatitis but from none of the control rats. Beads were visualized in 91% of the pancreata of rats with acute pancreatitis but in none of the pancreata from control rats. Beads were not visualized in the mesenteric lymph nodes of rats with acute pancreatitis, suggesting a transperitoneal route of migration. We conclude that acute pancreatitis promotes bacterial translocation leading to transperitoneal infection of the pancreas. These results support the use of selective decontamination of the gut and peritoneal lavage for the prevention of pancreatic infections in acute pancreatitis.

Rejection of ileal versus jejunal allografts.

Small-bowel allografts are replete with lymphocytes, which may be the main stimulus for the recipients immune system, thereby inducing rejection. Since most of the lymphoid tissue is located in the ileum, one would expect ileal grafts to be rejected more rapidly than are jejunal grafts. To test this theory, we transplanted a jejunal (n = 13) or an ileal segment (n = 9) or the entire small bowel (n = 6) orthotopically in the BN----LEW rat strain combination. Jejunal grafts included a short segment of the mesentery, whereas ileal and whole small-bowel grafts included the entire mesentery with its lymph nodes. Segmental as well as entire-bowel grafts induced peak anti-BN titers on the 6th to 7th postoperative day. In rats with entire-bowel grafts, rejection culminated in the recipients death after an average of 9.5 +/- 1 days from graft necrosis and peritonitis; the rejection of jejunal (13.1 +/- 2.1 days) and ileal grafts (12.9 +/- 1.3 days) was less rapid. Segmental grafts were often encapsulated, and the causes of death were inanition and intestinal obstruction. Thus, despite their high lymphocyte content, ileal grafts were not rejected more quickly than were jejunal grafts; they should, therefore, be preferred because of their greater specialized absorptive capacity. Histologically, entire-bowel grafts were found to be rejected as rapidly as were segmental grafts; however, the toxic effects of the larger grafts that are undergoing rejection lead to earlier death of the recipient.

Successful treatment of ongoing intestinal allograft rejection permits recovery of graft structure and function

Acute rejection episodes often complicate clinical small bowel transplantation, which prompted us to investigate whether such episodes can be reversed and the intestinal graft salvaged. Inbred Lewis rats that received fully allogeneic Brown-Norway small bowel allografts were treated with cyclosporin A (10 mg/kg) for 5 days, and the drug was then discontinued. Clinical and histologic signs of acute rejection developed, and the animals were subsequently treated with FK 506 (2 mg/kg) on days 14, 16, and 18. Survival was significantly prolonged (201.7 +/- 46.8 days) when compared with animals that were not administered FK 506 (16.5 +/- 0.8 days) or allograft recipients that received no immunosuppressive therapy (10.8 +/- 0.7 days). The histologic changes and functional impairment due to rejection that were observed prior to the start of the FK 506-therapy were reversed. However, biopsy specimens of all animals exhibited features of chronic rejection. This study provides evidence that acute rejection of intestinal allografts can be successfully treated with a short course of FK 506.

Mucosal recipient-type mononuclear repopulation and low-grade chronic rejection occur simultaneously in indefinitely surviving recipients of small bowel allografts

Lewis rat recipients of long-term, surviving, orthotopic Brown-Norway rat intestinal allografts, initially treated with cyclosporin A (CyA) or FK 506, were evaluated for their functional capacity and morphology over 1 year after the immunosuppressive therapy had been discontinued. Functional parameters such as nitrogen and fat balances, maltose absorption, blood chemistry, hematologic studies, and the weight gained by the allografted animals did not differ from those of syngeneically grafted or agematched normal animals. Immunohistochemical studies showed that the lamina propria of the allografts was repopulated with recipient MHC class II+mononuclear cells and that a normal distribution of T helper, T suppressor/killer, and IgA+plasma cells had occurred. However, fibrous replacement of the mesenteric lymph nodes and Peyers patches were detected in all, and an inflammatory obliterative arteriolopathy developed in the mesenteric vasculature of half of the allografted animals. No such findings were observed in recipients of syngeneic grafts. These results demonstrate that the limited use of potent immunosuppressive agents immediately after transplantation averts rejection and is followed by recipient-type mucosal lymphocytic repopulation. Simultaneously, a clinically not recognizable chronic rejection evolves. This suggests that the timely diagnosis of chronic rejection may not be possible with the use of standard tests of gut function and random mucosal biopsies alone.

Effect of cyclosporin therapy in controlling the rejection of ileal versus jejunal allografts

Abstract. Experimental evidence suggests that jejunal allografts are rejected as rapidly as are ileal grafts, despite their lesser content of lymphoid tissue as an immunologic stimulus. However, it may be possible to postpone the rejection of jejunal grafts more readily than that of ileal grafts by means of immunosuppressive therapy with cyclosporin (CyA). To test this, we used the rat model (BN‐LEW) of orthotopic small‐bowel transplantation. The proximal third of the small‐bowel with one‐third of the mesenteric lymph nodes (n= 20), or the distal ileal third with all of the mesenteric lymph nodes (n= 22), or the entire small‐bowel (n= 23) was interposed after resection of an equivalent type and length of recipient bowel. CyA (15 mg/kg) was given to all of these rats for 5 days. Three additional control groups were not given CyA. The difference in graft/recipient survival among the groups receiving CyA and among those not on CyA therapy was not statistically significant. Antidonor hemagglutinin titers, the mixed lymphocyte culture (MLC) assay, and histologic examination of the allograft failed to show a mitigated rejection reaction for the recipients of jejunal grafts. The data show that short‐term treatment with CyA prolongs graft survival. Equal doses of CyA, however, did not lead to prolonged survival of jejunal grafts or alter the course of rejection in comparison with that for ileal or whole‐bowel transplants.