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W Timmermann

Publications and source records attributed to W Timmermann.

At least 19 recordsLinked to original sources
PubMed2001

Influence of donor MHC class I antigen expression on graft survival after rat parathyroid allotransplantation.

BACKGROUND AND AIMS: We investigated the influence of donor MHC antigen expression on graft survival after parathyroid transplantation in three different strain combinations. METHODS: MHC class I and II expression on parathyroid tissue of Lewis (LEW), Dark Agouti (DA), and Wistar-Furth (WF) rats was first analysed semiquantitatively by immunohistochemistry. Additionally, five groups were transplanted: (1) LEW to LEW, (2) DA to DA, (3) LEW to DA, (4) WF to LEW, and (5) DA to LEW. METHODS: MHC class I expression was strong in DA, moderate in WF, and weak in LEW rats; MHC class II expression was negative in all three strains. In the interstitium of all investigated tissue specimens, the proportion of MHC class II-expressing cells was low. RESULTS: After syngeneic transplantation, graft survival could be documented over the whole observation period. A mean graft survival of 20 (+/-2) days was observed following transplantation from LEW to DA, grafts in the group WF to LEW were rejected after 13 (+/-1) days, and graft function lasted 8 (+/-2) days in the group DA to LEW. The number of intragraft leukocytes expressing MHC class II molecules was equal in all groups, whereas increased levels of MHC class I on rat parathyroid tissue before transplantation resulted in a more rapid rejection. CONCLUSION: These results demonstrate that immunogenicity of rat parathyroid tissue seems to be determined by the amount of MHC class I expressed on donor parenchymal cells.

Animals↗
PubMed2001

Persistence of stable intragraft cell chimerism in rat liver allografts after drug-induced tolerance.

BACKGROUND: Drug-induced tolerance of rat liver allografts is well documented. We analyzed cellular events during immunosuppressive therapy on day (d) 10 and in the late phase (d 100) after transplantation to assess for characteristics in the intrahepatic leukocyte (IHL) population in the phase of tolerance. METHODS: Lewis rats served as recipients of Dark Agouti rat livers. Temporary immunosuppression with either cyclosporine (CsA) monotherapy (3 mg/kg/d) or triple therapy that consisted of a subtherapeutic CsA dosage (0.25 mg/kg/d) and monoclonal antibodies directed against the interleukin-2 receptor (IL-2R, CD25) and the intercellular adhesion molecule-1 (ICAM-1, CD54) was administered from postoperative d 0 to d 13. Cell migration and cell activation within liver grafts was assessed by standard histology and flow cytometry. IHL apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling (TUNEL). RESULTS: Both CsA monotherapy and triple therapy prolonged liver allograft survival to more than 100 d and led to the induction of donor-specific tolerance. Untreated recipients rejected their allografts within 14 d. In both groups, donor-specific IHLs initially dropped to 18% to 25% on d 10, but they rebounded to as much as 40% on d 100 as a common characteristic of both groups. Within this population, donor-specific T cells were dominant. In both groups, increased numbers of activated (IL-2R+) CD8+ T lymphocytes were present on d 100. No accumulation of apoptotic IHL was observed on d 100. Their proportion was unchanged in the triple therapy group and slightly decreased in the CsA group compared to the syngeneic controls. CONCLUSIONS: The present study reveals that tolerant liver allografts are repopulated by donor-specific T lymphocytes. This phenomenon is independent of the type of applied immunosuppression. The persistence of activated CD8+ T cells in the phase of proven donor-specific tolerance on d 100 indicates that liver tolerance is associated with the state of a permanent intragraft immune activation. It seems that the coexistence of donor cells with infiltrating recipient cells within liver grafts, termed intrahepatic cell chimerism, is characteristic for tolerated liver allografts.

Animals↗
PubMed2001

Orthotopic liver/small bowel transplantation in rats: a microsurgical model inducing tolerance.

Liver cirrhosis in patients with short bowel syndrome is successfully treated in humans by simultaneous liver/small bowel transplantation. However, until now, a clinically relevant experimental rat model for this procedure has not existed. We therefore established a protocol that, for the first time in rats, allows the simultaneous transplantation of arterialized liver and small bowel into an orthotopic position. Short-term immunosuppression induced not only allograft acceptance but tolerance (as demonstrated by indicator heart/skin transplantation). The immunosuppressive dose required to achieve this result was dramatically less than that of protocols for successful small bowel transplantation alone. Immunohistochemistry detected a transient rejection crisis before tolerance. During this crisis, apoptotic recipient-type T lymphocytes, mainly CD8+ cells, accumulated in the liver but not in the small bowel allograft. The initiation of T-cell apoptosis is one possible explanation for the specific immunosuppressive effect of the liver allograft, which also supports the simultaneously transplanted small bowel allograft in our model.

Animals↗
PubMed2001

Rat parathyroid allotransplantation: Influence of MHC antigen expression on graft survival.

MHC antigen expression in parathyroid tissue and its influence on graft survival after allogeneic transplantation were investigated using a heterotopic rat transplantation model. MHC class I and II expression in parathyroid tissue of Lewis (LEW), Dark Agouti (DA), and Wistar-Furth (WF) rats was analysed semi-quantitatively by using immunohistochemistry. MHC class I expression was strong in DA, moderate in WF, and weak in LEW rats parenchyma, whereas MHC class II expression was negative. In the interstitium of all investigated tissue specimens, the proportion of MHC class II-expressing cells was low. Additionally, four groups were transplanted: 1) LEW to LEW, 2) DA to DA, 3) LEW to DA, and 4) WF to LEW. After syngeneic transplantation, graft survival could be documented over the whole observation period. A median graft survival of 20 (+/-2) days was observed after transplantation from LEW to DA, whereas grafts in the group WF to LEW were rejected after 13 (+/-1) days. The number of intra-graft leucocytes expressing MHC class II molecules was the same in all groups, whereas increased levels of MHC class I in parathyroid tissue before transplantation resulted in a more rapid rejection. These results indicate that immunogenicity of rat parathyroid tissue might be determined by the amount of MHC class I expressed in donor parenchymal cells. Further experiments are necessary to validate this observation.

Animals↗
PubMed2001

[Restoration of blood circulation in reperfusion of ischemic tissues].

In experiment there were studied changes of the tissue blood circulation and microcirculation during postischemic reperfusion of skeletal muscles with various density of capillaries. It was established that reactive hyperemia, caused mainly by enhancement of extracapillary tissue blood flow. While persistence of durable arterial hypertension the capillaries quantity and potential volume of microcirculatory bed are reducing, negatively influencing the blood circulation restoration process during postischemic reperfusion. In chronic ischemia the potential volume of microcirculation is increasing, securing complete restoration of blood circulation in postischemic reperfusion.

Animals↗
PubMed2000

Tolerance of rat liver allografts induced by short-term selective immunosuppression combining monoclonal antibodies directed against CD25 and CD54 with subtherapeutic cyclosporine.

BACKGROUND: Our purpose was to develop and evaluate protocols for selective immunosuppression after liver transplantation using the monoclonal antibodies (mAbs) NDS-61, directed against the interleukin-2 receptor (CD25), and 1A29, directed against the intercellular adhesion molecule-1 (CD54), in combination with subtherapeutic cyclosporine (CsA). METHODS: Orthotopic rat liver transplantation (ORLT) was performed in a DA-to-LEW strain combination. Immunosuppression was administered from day 0 to +13. Functional parameters such as survival time, body weight, and serum bilirubin levels were measured and the liver grafts were evaluated histologically. RESULTS: A stepwise tapering of CsA from 3 to 0.25 mg/kg/day reduced the long-term survival rate. All animals died at a CsA dosage of 0.25 mg/kg/day, which was therefore defined as subtherapeutic. Monotherapy with the anti-CD25 mAb was performed at dosages of 600 and 1800 microg/kg/day. The lower mAb dosage resulted in a long-term survival rate of 12% and was defined as subtherapeutic. The combination therapy of CsA (0.25 mg/kg/day) and anti-CD25 mAb (600 microg/kg/day) produced a synergistic effect and led to a long-term survival rate of 84%. This survival rate was significantly higher than those after either CsA (P<0.005) or anti-CD25 mAb (P<0.001) monotherapy. Both dosages (10 and 30 microg/kg/day) of anti-CD54 mAb monotherapy as well as anti-CD54 mAb combined with a subtherapeutic dosage of CsA were ineffective in preventing acute allograft rejection. The addition of anti-CD54 mAb (30 microg/kg/day) to combined CsA plus anti-CD25 mAb therapy (triple therapy), however, increased the long-term survival rate to 100%. In the triple therapy group there was no rejection process in the liver allografts at any time, and donor-specific tolerance could be shown by donor-specific and third-party heterotopic heart transplantation. CONCLUSIONS: The synergistic action of subtherapeutic CsA plus anti-CD25 mAb NDS-60 could be demonstrated, whereas anti-CD54 mAb only had a positive effect in a triple therapy group. Triple therapy prevented both acute and chronic rejection and induced donor-specific tolerance.

Animals↗
PubMed2000

Donor-derived alloantigen-presenting cells persist in the liver allograft during tolerance induction.

The predictive value of chimerism was evaluated in three different transplantation models in the rat without immunosuppression: small bowel- (SBTx), liver- (LTx), and liver/small bowel transplantation (LSBTx) were performed in the Brown Norway (BN)-to-Lewis-(LEW) strain combination. Immunohistochemistry and flow cytometry were used to identify donor cells in the recipient's spleen. Their number did not change significantly during transient rejection or tolerance after LTx and LSBTx. However, the amount of donor-derived nonparenchymal cells within the liver allograft including antigen-presenting cells (APCs), such as dendritic and Kupffer cells, clearly mirrored the recipient's immune status: as expected, their number decreased during rejection, but recovered considerably during and after tolerance induction. We conclude that donor cells in the periphery of the recipient correlate with the presence of the allograft, but do not seem to influence graft acceptance actively. However, the kinetics of the detected donor APC population in the liver suggests their important role in modifying the recipient's immune response towards tolerance.

Animals↗
PubMed2000

"Tolerogenic effect" of the liver for a small bowel allograft.

A newly developed liver/small bowel transplantation model (LSBTx) was used to investigate the tolerogenic effect of a liver allograft toward a simultaneously transplanted small bowel. Small bowel transplantation (SBTx) under high-dose immunosuppression was compared to LSBTx with a lower FK506 dosage. Syngeneic Lewis [(LEW) to LEW] and two fully allogeneic rat strain combinations (Brown Norway-to-LEW and Dark Agouti-to-LEW) were used. Clinical course and histological findings after SBTx demonstrated a chronic rejection of the small bowel allograft within 100 days. However, after LSBTx long-term acceptance (> 150 days) was achieved after a transient rejection crisis, although initial immunosuppression was significantly lower. Furthermore, indicator heart transplantations demonstrated the induction of donor-specific tolerance in both allogeneic strain combinations. In contrast to other LSBTx rat models, these results reflect observations after human LSBTx, in which the rate of acute and chronic rejection is also significantly lower than after human SBTx.

Acute Disease↗
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

Different kinetics of donor cell populations after isolated liver and combined liver/small bowel transplantation.

Spontaneous tolerance induction after liver transplantation also supports additional transplants, e.g. a small bowel graft, from the same donor (tolerogenic effect). Chimerism serves as a possible explanation of this phenomenon. Isolated liver (LTx) and combined liver/small bowel transplantation (LSBTx) are compared. LSBTx and LTx were performed in the BN --> LEW rat strain combination without immunosuppression. Parenchymal damage during rejection was monitored by sequential standard histology. Donor/recipient populations were identified and further differentiated for immunohistochemical single and double staining. A small number of donor specific leukocytes can be detected on all days in host organs (microchimerism). A significantly larger donor leukocyte population survives long-term in the sinusoids of liver (graft chimerism). Sinusoidal donor leukocytes survive rejection and recover in number after tolerance induction. Rejection of liver allografts and infiltration by host leukocytes are more pronounced after LSBTx than after LTx. Accordingly, during rejection a steeper decline of sinusoidal donor leukocytes is observed after LSBTx and recovery after tolerance induction is not as marked. Microchimerism apparently plays no significant role in either transplantation model. The number of sinusoidal donor leukocytes, however, mirrors closely host immune responses.

Animals↗
PubMed2000

[Adjuvant immunotherapy of stomach carcinoma with antibody-induced apoptosis].

The human monoclonal antibody SC-1 was isolated from a patient with a diffuse-type adenocarcinoma of the stomach and induces apoptosis of stomach carcinoma cells by binding a stomach-carcinoma-associated isoform of CD55/DAF-B. In a first clinical trial with 20 patients with poorly differentiated stomach adenocarcinoma of diffuse-type received 20 and 30 mg of purified SC-1 antibody intravenously, followed 24 or 48 h later by gastrectomy and lymphadenectomy. In 90% of the cases a significant induction of apoptotic activity was measured in primary tumors as compared with earlier biopsy material and in 50% of the patients a significant regression of tumor mass could even be determined histopathologically. No toxic crossreactivity was observed with normal tissue or organs of patients. These data show, that the human monoclonal antibody SC-1, which induces tumorspecific apoptosis, can be successfully used for adjuvant therapy.

Adenocarcinoma↗
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

Helical CT cholangiography for the detection and localization of bile duct leakage.

OBJECTIVE: We describe the use of helical CT cholangiography or helical CT after administration of biliary i.v. contrast material to verify and localize bile duct leakage. CONCLUSION: Helical CT cholangiography revealed bile leaks in seven patients after penetrating trauma or liver or gallbladder surgery and excluded bile leaks in two patients with blunt liver trauma. Endoscopic retrograde cholangiography was performed in only one of seven patients with bile leakage and was avoided in an additional two patients in whom CT cholangiography excluded leakage. The method is a feasible, noninvasive tool for the detection and localization of bile leaks and may help avoid endoscopic retrograde cholangiography.

Adult↗