The use of FK-506 for small intestine llotransplantation: Inhibition of acute rejection and prevention of fatal graft-versus-host disease

Small intestine allotransplantation in humans is not yet feasible due to the failure of the current methods of immunosuppression. FK-506, a powerful new immunosuppressive agent that is synergistic with cyclosporine, allows long-term survival of recipients of cardiac, renal, and hepatic allografts. This study compares the effects of FK-506 and cyclosporine on host survival, graft rejection, and graft-versus-host-disease in a rat small intestine transplantation model. Transplants between strongly histoincompatible ACI and Lewis (LEW) strain rats, and their Fi progeny are performed so that graft rejection alone is genetically permitted (F1→LEW) or GVHD alone permitted (LEW→F1) or that both immunologic processes are allowed to occur simultaneously (ACI—»LEW). Specific doses of FK-506 result in prolonged graft and host survival in all genetic combinations tested. Furthermore, graft rejection is prevented (ACI→LEW model) or inhibited (rejection only model) and lethal acute GVHD is eliminated. Even at very high doses, cyclosporine did not prevent graft rejection or lethal GVHD, nor did it allow long-term survival of the intestinal graft or the host. Animals receiving low doses of cyclosporine have outcomes similar to the untreated control groups. No toxicity specific to FK-506 is noted, but earlier studies by other investigators suggest otherwise. © 1990 by Williams & Wilkin

Evidence for hyperacute rejection of human liver grafts: The case of the canary kidneys

Sequential liver and kidney transplantation from the same donor was performed in 2 patients. The kidney in Patient 1, which was transplanted after the liver, was hyperacutely rejected and removed 6 hours later. The first liver as well as another liver transplanted 3 days later developed widespread hemorrhagic necrosis. Although the cytotoxic crossmatch of preoperative recipient serum with both donors was negative, patchy widespread IgM and C(1q) deposits were found in all 3 organs. In Patient 2, who had a strongly positive cytotoxic crossmatch with his donor, the liver suffered a massive but reversible injury, while the kidney never functioned. Both patients developed a coagulopathy a few minutes after liver revascularization. The kidneys in these cases had served like the canaries which miners once used to detect a hostile environment and their presence made more understandable how an indolent version of hyperacute rejection of the liver can take place

Is rejection a diffuse or localized process in small-bowel transplantation?

Utilization of endoscopy to both visualize and selectively biopsy an intestinal allograft has become the standard for early recognition and treatment of intestinal allograft rejection. Despite the widespread acceptance of the need for selective mucosal biopsies, it has not been shown that the histological features of intestinal allograft rejection are either localized or occur as part of a more diffuse phenomenon within a tubular allograft. To resolve these issues, 88 ileoscopies were performed in 12 small-bowel allograft recipients and mucosal biopsy samples were obtained at 5, 10, and 15 cm, respectively, from the ileal stoma. Each mucosal biopsy was labeled, processed, and evaluated individually for the presence and severity of any evidence for allograft rejection. The data obtained suggest that intestinal allograft rejection is a diffuse process, and biopsies obtained randomly from an ileal graft are likely to demonstrate evidence of allograft rejection when such is present. © 1994 Springer-Verlag New York Inc

Acute Thiopurine Overdose: Analysis of Reports to a National Poison Centre 1995-2013

Literature regarding acute human toxicity of thiopurines is limited to a handful of case reports. Our objectives were to describe all cases of overdose with thiopurines reported to the Swiss Toxicological Information Centre between 1995–2013. A retrospective analysis was performed to determine circumstances, magnitude, management and outcome of overdose with these substances. A total of 40 cases (14 paediatric) were reported (azathioprine, n = 35; 6-mercaptopurine, n = 5). Of these, 25 were with suicidal intent, 12 were accidental and 3 were iatrogenic errors. The magnitude of overdose ranged from 1.5 to 43 (median 8) times the usual dose in adults. Twelve cases (30%) had attributable symptoms. The majority of these were minor and included gastrointestinal complaints and liver function test and blood count abnormalities. Symptoms were experienced by patients who took at least 1.5-times their usual daily thiopurine dose. Overdoses over two or more consecutive days, even if of modest size, were less well tolerated. One case of azathioprine and allopurinol co-ingestion over consecutive days led to agranulocytosis. Decontamination measures were undertaken in 11 cases (10 activated charcoal, 1 gastric lavage) and these developed fewer symptoms than untreated patients. This study shows that acute overdoses with thiopurines have a favourable outcome in the majority of cases and provides preliminary evidence that gastrointestinal decontamination with activated charcoal may reduce symptom development after overdose of these substances if patients present to medical services soon after ingestion

Immunodepletion in xenotransplantation

Xenograft transplantation is perhaps the most immunologically difficult problem in transplantation today. An overwhelming hyperacute rejection reaction (HAR) occurs within minutes of organ implantation. Preformed antibodies are thought to initiate this process. We used a pig-to-dog renal xenograft transplant model and investigated methods of decreasing the severity of hyperacute rejection. Female pigs weighing 15-20 kg were used as donors. Recipients were mongrel dogs weighing 15-25 kg. Experimental dogs were all given a number of treatments of IgG depletion using an antibody removal system (Dupont-Excorim). This machine immunoadsorbs plasma against a column containing immobilized staphylococcal protein A, which is known to bind the IgG Fc receptor. An 84% reduction in the IgG levels and a 71% reduction in IgM levels was achieved. Postoperative assessment was made of urine output, time to onset of HAR, and histopathological examination of the rejected kidneys. Although cross-matches between donor lymphocytes and recipient sera remained strongly positive in the treated dogs, there was a two- to fourfold reduction in the titers. The time to onset of HAR was prolonged in the experimental group, and the urine output was increased slightly. The histopathologic changes in the experimental group generally showed signs of HAR, but of less intensity than in the nonimmunodepleted control group. © 1990 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted

Induction of stable chimerism and elimination of graft-versus-host disease by depletion of T lymphocytes from bone marrow using immunomagnetic beads

The goal of transplantation is the induction of immunologic tolerance. At present, nonspecific immunosuppression is used to prevent graft rejection and, commonly, graft-versus-host disease (GVHD). Nevertheless, nonspecific immunosuppressive therapy is frequently complicated by infection, malignant tumors, and drug toxicity. In order to examine whether hematopoietic chimerism can be used to induce specific allograft tolerance, we have reconstituted lethally irradiated Lewis rats with ACI bone marrow that has been depleted of T cells with use of immunomagnetic beads. This technique consists of binding OX-19, a mouse anti-rat pan- T lymphocyte monoclonal antibody, to magnetic polymer beads. Mixing of bone marrow or splenocytes with the bead/OX-19 complexes, followed by magnetic separation, results in significant depletion of T cells with minimal nonspecific cell loss. Immunomagnetic T-cell depletion of bone marrow, followed by reconstitution of a lethally irradiated host, allows for the development of stable, mixed hematopoietic chimerae without evidence of GVHD. These hosts are immunocompetent by clinical criteria. Recipients of untreated donor bone marrow that did or did not receive nonspecific immunosuppression demonstrated varying degrees of GVHD and reduced survival. The ability to rapidly and simply deplete T lymphocytes from bone marrow and produce stable, immunocompetent hematopoietic chimerae without GVHD may be an important method for tolerance induction to vascularized allografts. © 1989

Transverse mass and invariant mass observables for measuring the mass of a semi-invisibly decaying heavy particle

Formulae are derived for the positions of end-points in the invariant mass and transverse mass distributions obtained from the products of heavy states decaying to pairs of semi-invisibly decaying lighter states. Formulae are derived both for the special case where the two decay chains are identical and the more general case where they are different. The formulae are tested with a simple case study of heavy SUSY higgs particles decaying to gauginos at the LHC.Comment: 13 pages, 8 eps figure