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Biomedical subjects

M Gasser

Publications and source records attributed to M Gasser.

At least 19 recordsLinked to original sources
PubMed2001

Regulatory functions of self-restricted MHC class II allopeptide-specific Th2 clones in vivo.

We studied T-cell clones generated from grafts of rejecting and tolerant animals and investigated the regulatory function of Th2 clones in vitro and in vivo. To prevent allograft rejection, we treated LEW strain recipient rats of WF strain kidney grafts with CTLA4Ig to block CD28-B7 costimulation. We then isolated epitope-specific T-cell clones from the engrafted tissue, using a donor-derived immunodominant class II MHC allopeptide presented by recipient antigen-presenting cells. Acutely rejected tissue from untreated animals yielded self-restricted, allopeptide-specific T-cell clones that produced IFN-gamma, whereas clones from tolerant animals produced IL-4 and IL-10. Adoptive transfer into naive recipients of Th1 clones, but not Th2 clones, induced alloantigen-specific delayed-type hypersensitivity (DTH) responses. In addition, Th2 clones suppressed DTH responses mediated by Th1 clones in vivo and blocked Th1 cell proliferation and IFN-gamma production in vitro. A pilot human study showed that HLA-DR allopeptide-specific T-cell clones generated from patients with chronic rejection secrete Th1 cytokines, whereas those from patients with stable graft function produce Th2 cytokines in response to donor-specific HLA-DR allopeptides. We suggest that self-restricted alloantigen-specific Th2 clones may regulate the alloimmune responses and promote long-term allograft survival and tolerance.

Animals↗
PubMed2000

Analysis of cellular events in hepatic allografts: donor progenitors induce intragraft chimerism.

Long-term graft acceptance and tolerance induction after allogeneic rat liver transplantation are well described. However, the underlying mechanisms remain unclear. In this study we investigated the cellular events within the liver graft during initial immunosuppression and long-term acceptance. Orthotopic liver transplantation was performed in the Dark Agouti (DA)-to-Lewis (LEW) and LEW-to-DA rat strain combination. In order to achieve long-term acceptance, LEW recipients of DA livers were treated with two different short-term therapies. Non-parenchymal cells (NPC) were isolated from liver allografts on days + 10 and + 100 after transplantation and donor-specific leukocytes were immunophenotyped by flow cytometry. Both the monotherapy and triple therapy prolonged graft survival (> 100 days). Liver allografts from LEW donors into DA recipients were spontaneously accepted across a complete MHC mismatch without immunosuppression. Liver allograft rejection was induced by infiltrating alloreactive immunocompetent cells. But the intensities of cell infiltration in the early and late phases after transplantation did not correlate with eventual outcome. Donor-specific NPC decreased to 18-25% on day + 10 in both therapeutic groups, but had rebounded to up to 40% by day + 100. Recurrence of donor-specific cells was caused almost exclusively by rising T cell counts. The persistence of dendritic cells in the late phase after transplantation could be clearly demonstrated. Repopulation by donor-specific T lymphocytes was observed in long-term accepted liver grafts. This recurrence may be based on the differentiation of liver-derived progenitor cells. The persistent coexistence of donor and recipient cells within the liver allograft (intrahepatic chimerism) appears to be characteristic and may be important for long-term acceptance.

Animals↗
PubMed2000

Long-term small bowel allograft function induced by short-term FK 506 application is associated with split tolerance.

Functional long-term allograft survival after experimental small bowel transplantation (SBT) is limited by chronic rejection. Initial application of high-dose FK 506 has been shown to induce stable long-term graft function. In order to examine whether this long-term function is associated with donor-specific tolerance, we analyzed the functional status of recipient T cells in vivo and in vitro. One-step orthotopic SBT was performed in the allogeneic Brown Norway (BN)-to-Lewis rat strain combination. FK 506 was given daily at a dose of 2 mg/kg from days 0-5 in the rejection model and from days 0-9 in the long-term functional model. Mean survival time in the rejection model was 98 +/- 2.8 days. Histological examination of these small bowel allografts disclosed signs of chronic rejection. In contrast, all animals of the long-term functional model survived long term (> 250 days) without clinical signs of chronic rejection. The latter model, furthermore, produced evidence of donor-specific tolerance. Whereas heterotopic Dark Agouti (DA) hearts were rejected regularly within 7 days, BN hearts survived indefinitely (> 70 days). In vitro, mixed leukocyte reactivity of CD4+ T cells was similarly strong against donor (BN) antigens as against third-party (DA) antigens. The split tolerance revealed by our in vivo and in vitro results enabled acceptance of both the small bowel allograft without signs of chronic rejection and of donor-specific heart allografts.

Animals↗
PubMed2000

Mechanisms of chronic rejection.

Chronic rejection remains the major obstacle to long-term allograft survival. Detailed understanding of putative etiologic risk factors, both antigen-dependent and -independent, is important for designing effective therapeutic strategies to ameliorate this process. Cell senescence may be an important factor in chronic rejection.

Animals↗
PubMed2000

Life-history correlates of evolution under high and low adult mortality.

Life-history theory predicts evolutionary changes in reproductive traits and intrinsic mortality rates in response to differences in extrinsic mortality rates. Trade-offs between life- history traits play a pivotal role in these predictions, and such trade-offs are mediated, at least in part, by physiological allocations. To gain insight into these trade-offs, we have been performing a long-term experiment in which we allow fruitflies, Drosophila melanogaster, to evolve in response to high (HAM) and low (LAM) adult mortality rates. Here we analyze the physiological correlates of the life-history trade-offs. In addition to changing development time and early fecundity in the direction predicted, high adult mortality affected three traits expressed early in life-body size, growth rate, and ovariole number-but had little or no effect on body composition (relative fat content), viability, metabolic rate, activity, starvation resistance, or desiccation resistance. Correlations among lines revealed trade-offs between early fecundity, late fecundity, and starvation resistance, which appear to be mediated by differential allocation of lipids.

Animals↗
PubMed2000

Molecular and cellular events associated with ischemia/reperfusion injury.

I/R is an important non-specific, antigen independent event, which significantly influences the outcome of transplanted organs. Increasing graft immunogenicity and host alloresponsiveness inflicts additional deleterious effects. Ischemia has also been associated with donor conditions such as brain death and the non-heart-beating donor. As an event surrounding organ procurement, preservation and revascularization occurring early in the transplant process, it initiates a cascade of molecular and cellular events which trigger the release of proinflammatory mediators and attraction of various cell types infiltrating the tissues. This inflammatory event influences both acute functional and structural changes in the organ which contributes to reduced graft survival. Eventually, attenuation of I/R by strategies targeting various mediators and cell populations at different levels of the inflammatory cascade may constitute a means to improve both short and long-term success of solid organ grafts.

Blood Platelets↗
PubMed2000

The influence of donor brain death on short and long-term outcome of solid organ allografts.

Long-term survival rates of solid organ allografts have improved relatively little during the transplant experience despite more effective immunosuppression, better organ preservation techniques and advances in perioperative management. Because grafts of potentially diminished quality are increasingly accepted to reduce the severe shortage of organs, it has become apparent that a variety of donor-associated risk factors may influence adversely their short and long-term outcome. Recent interest has focused particularly on systemic changes occurring after donor brain death (BD). Numbers of experimental and clinical studies have elucidated the complexities of the hemodynamic, metabolic, neurohormonal, and other physiological alterations following this devastating central injury. This article will address the potential derangements in peripheral organs which may influence their behavior after transplantation.

Brain Death↗
PubMed1999

Videomicroscopic imaging of graft mucosa for monitoring immunosuppressive therapy after small intestinal transplantation in rats.

BACKGROUND: Early diagnosis of rejection and effective immunosuppressive treatment are essential after small intestinal transplantation. To date little is known about microscopic alterations of the intestinal mucosa of the graft during rejection. We attempted to determine whether videomicroscopic imaging of the graft mucosa is a suitable method for monitoring immunosuppressive therapy. METHODS: Real-time videomicroscopic imaging of an ileostoma was performed daily after allogeneic heterotopic small bowel transplantation in the rat (BN to LEW) with and without FK506 immunosuppression. Subsequently, the videomicroscopic findings were compared with the histologically determined grade of rejection. RESULTS: A semiquantitative staging system was established for the intravital mucosal changes during graft rejection. The earliest changes related to rejection appeared on POD 6 in the untreated allogeneic group. The mucosa developed patchy paleness and the mucosal architecture was interrupted in places. The crypts were slightly widened and their color turned dark red (stage I). These alterations spread progressively over the mucosa on POD 7 (stage II). On POD 9 the mucosa appeared pale, the villi were shortened, and the crypts appeared wide and rounded (stage III). In the animals treated with FK506 similar changes were observed, but with a delayed onset. When FK506 was administered as antirejection therapy at the onset of rejection, a temporary improvement of mucosal alterations was observed (stage II --> stage I). The video-microscopic stages correlated with the histological grade of rejection. CONCLUSIONS: The introduction of videomicroscopy has made computer-based high resolution imaging of mucosal microarchitecture possible. With videomi-croscopy beginning rejection can be detected, although it can still be reversed with antirejection therapy. This is a new noninvasive technique that might be of high clinical relevance.

Acute Disease↗
PubMed1999

Noninvasive videomicroscopic monitoring of rat small-bowel rejection.

Successful small-bowel transplantation requires an early diagnosis of graft rejection. To date, little is known about macroscopic mucosal alterations during rejection. In the present study, these changes were analyzed in detail. Videomicroscopic monitoring of an enterostoma was performed after allogeneic heterotopic small-bowel transplantation in the rat (BN to LEW). Up to postoperative day (POD) 3 a mucosal edema was noticed (stage I of videomicroscopical alterations). The earliest changes related to rejection appeared on POD 6. The mucosa of the grafted intestine developed patchy paleness and interruptions in mucosal architecture. Crypts were slightly widened and their color turned to dark red (stage IIa). Progressively, these alterations spread over the mucosa on POD 7 (stage IIb). On POD 9, the mucosa appeared pale, villi were shortened, and crypts appeared wide and rounded. The mucosal surface was coated with fibrinous membranes (stage III). The videomicroscopic findings were closely related to the histological grading of rejection. We regard this technique of mucosal monitoring a simple and noninvasive method of detecting allograft rejection.

Animals↗
PubMed1999

The first case report of the use of a zoom videoendoscope for the evaluation of small bowel graft mucosa in a human after intestinal transplantation.

BACKGROUND: Control of allograft rejection remains the most difficult dilemma in intestinal transplantation. Standard endoscopic surveillance to date has not been always accurate in the diagnosis of rejection. We describe the first application of a zoom video endoscope in monitoring graft mucosa in humans after intestinal transplantation. METHOD: A zoom video endoscope, which can magnify the image up to 100-fold, was used in this study. The patient was a 31-year-old man who received an isolated intestinal transplant. Surveillance endoscopy with the zoom video endoscope was performed through the ileostomy. Endoscopic biopsies were done at the same time. RESULTS: The zoom video endoscope showed the microscopic architecture of the graft mucosa such as villi and crypts with outstanding quality. We found that an enlargement of the crypt areas appeared to correlate with morphologic changes of early rejection. This finding was reversed with the treatment of rejection. CONCLUSIONS: The zoom video endoscope successfully showed the detailed information of intestinal mucosa. The ability to visualize a more representative view of the graft mucosa could lead to better detection of early rejection. A greater experience with this unique method will provide more accurate assessment of the intestinal allograft.

Adult↗
PubMed1998

[Economic evaluation in a trial of medically controlled prescription of narcotics to dependent users (PROVE)].

In the 1994-1996 trial of medically controlled prescription of narcotics to dependent users, 800 places were ascribed to heroin substitutes and another 200 for methadone and morphine substitutes. The trial was evaluated with the aid of an accompanying research. Among the results demonstrated in the evaluation was an improvement of the health of the participants. The economic assessment was drawn from observations of health effects within a sub-sample of 142 participants from four centers. In a retrospective statistical survey, for each acute illness which could be influenced through the trial, the number of diagnoses was recorded in the first and thirteenth month after study entry. Also, based on a number of representative cases for each of these acute illnesses, the resource use, i.e. the types and numbers of medical products and services rendered to the patients, was recorded. The results showed a clear decline in depressive episodes, skin diseases, digestive system disorders as well as epileptic attacks and intoxication. Treatment costs could be reduced from a total of CHF 94875.--to CHF 21,998.--/month or from CHF 22.27 to CHF 5.15/patient per day. The improvement of somatic and psychic health due to the medically controlled prescription of narcotics resulted in a benefit of CHF 17.11/person per day.

Depression↗