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Biomedical subjects

S Korom

Publications and source records attributed to S Korom.

At least 19 recordsLinked to original sources
PubMed2006

Ischemia/reperfusion injury: The role of CD26/dipeptidyl-peptidase-IV-inhibition in lung transplantation.

UNLABELLED: CD26/Dipeptidyl peptidase (DPP) IV is an integral membrane protein of lymphocytes that modulates the activities of chemokines, interleukins, and neuropeptides. We investigated the effect of enzymatic DPP IV inhibition on ischemia/reperfusion injury after extended ischemia prior to transplantation. MATERIALS AND METHODS: We used a syngeneic rat (Lewis) orthotopic left lung transplantation model. In the control group (group I), donor lungs were flushed and preserved in Perfadex for 18 hours at 4 degrees C, then transplanted and reperfused for 2 hours. Group II donor lungs were perfused with and stored in Perfadex +25mol/L AB192 (bis(4-acetamidophenyl) 1-(S)-prolylpyrrolidine-2(R,S)-phosphonate), a small molecular weight DPP IV inhibitor. After 2-hour reperfusion, we measured blood gas, peak airway pressure, and thiobarbituric acid reactive substances. RESULTS: Grafts from group II versus group I showed a significantly increased oxygenation capacity (II: 298.4 +/- 87.6 mm Hg vs 120.9 +/- 48.0, P < .01), lower peak airway pressure (11.8 +/- 0.9 mm Hg vs 16.0 +/- 1.4, P < .01), and less lipid peroxidation (9.3 +/- 2.0 micromol/L vs 13.8 +/- 1.8, P < .01). CONCLUSION: Inhibition of intragraft DPP IV enzymatic activity significantly reduced ischemia/reperfusion-associated pulmonary injury, allowing for successful transplantation after 18 hours of ischemia.

Animals↗
PubMed2005

Surgery for non-localized bronchiectasis.

BACKGROUND: Resection for localized bronchiectasis is a well established therapy. However, there is little information on the role of surgery in non-localized bronchiectasis. METHODS: Between January 1992 and April 2001, 55 patients without cystic fibrosis underwent resection. Forty-eight patients (mean age 45 (range 23-74) years; 32 women) were available for long-term follow-up. Twenty-five patients underwent resection for localized disease (group 1) and 23 had bronchiectasis in at least two different lobes (group 2). RESULTS: Thirty-one of the 48 patients were treated by Video Assisted Thoracoscopic Surgery (VATS) resection. There was no 30-day mortality. Mean duration of hospital stay was 10.9 (range 6-31) days in group 1 and 11.1 (range 5-19) days in group 2. Three of 25 patients in group 1 required reoperation. Only minor complications occurred in group 2 (three patients). Mean follow-up for both groups was 37 (range 6-97) months. Twenty-three of 25 patients in group 1 and 16 of 23 in group 2 reported satisfaction at 6 months after the operation. Recurrent infection was noted in three patients in each group. Haemoptysis recurred in only one patient in group 2. CONCLUSION: The surgical treatment of selected patients with non-localized bronchiectasis was safe and most patients were satisfied with the outcome.

Adult↗
PubMed2001

Accelerated treatment for early and late postpneumonectomy empyema.

BACKGROUND: Postpneumonectomy empyema is a rare but serious complication of pneumonectomy. Despite use of various therapeutic approaches and techniques during the last five decades, successful therapy remains difficult and is often associated with high morbidity and prolonged hospitalization. METHODS: We evaluated a concept for accelerated treatment, which consists of radical debridement of the pleural cavity and packing with wet dressings of povidoneiodine. This was repeated in the operating theater every second day, until the chest cavity was macroscopically clean. If present, bronchial stump insufficiency was closed and secured by omentopexy. Finally, the pleural space was obliterated with antibiotic solution. RESULTS: Twenty patients, 13 with early postpneumonectomy empyema (10 to 89 days; mean, 37 days) and 7 with late postpneumonectomy empyema (124 to 7,200 days; mean, 1,126 days) were treated. Fifteen patients presented with bronchopleural fistula (11 right, 4 left), which developed after chemotherapy (n = 6) or after radiotherapy (n = 3) (unknown cause in 4 patients). Six patients were referred after previously unsuccessful surgical attempts. Pleural cultures were positive in 17 cases for one or several bacteria including fungoides (n = 2). The average number of interventions was 3.5 (3 to 5). The chest was definitively closed in all patients within 8 days. Mean hospitalization time was 17 days (7 to 35 days). During the same hospitalization, 2 patients needed reoperation because of an undetected bronchopleural fistula. Postpneumonectomy empyema was successfully treated in all patients. There was no in-hospital or 3-month postoperative mortality. CONCLUSIONS: Repeated surgical debridement combined with closure of bronchopleural fistula and antimicrobial therapy enables successful treatment of early and late postpneumonectomy empyema within a short period and is a well-tolerated concept.

Adult↗
PubMed2000

Evidence against a pivotal role of preformed antibodies in delayed rejection of a guinea pig-to-rat heart xenograft.

INTRODUCTION: Whereas the involvement of elicited xenoantibodies in delayed xenograft rejection is currently being substantiated, this study focuses on the role of the preformed fraction of xenoantibodies. METHODS: To check the influence of the latter, we combined pretransplant complement inactivation (cobra venom factor) and antibody reduction (plasmapheresis) in a guinea pig-to-rat heart transplant model. RESULTS: Antibody reduction on plasmapheresis before xenografting did not prolong delayed xenorejection in decomplemented rats, although the immunohistologic pattern lacked the immunoglobulin deposits along endothelial walls found in xenografts of merely decomplemented recipients. Astonishingly, plasmapheresis, if carried out 2 days before transplantation, almost tripled xenograft survival, although preformed antibody levels were completely restored and even rebounding at the time of grafting. The pattern and number of infiltrating cells did not differ in dependence of the timing of plasmapheresis nor did the proliferative response of lymphocytes in the mixed lymphocyte reaction differ. However, plasmapheresis led to a retarded decrease of the mononuclear cell tumor necrosis factor alpha secretory potential, which correlated well with a diminished immunohistologic staining of tumor necrosis factor alpha secreted by graft-infiltrating mononuclear cells. CONCLUSION: These findings argue against a pivotal role of preformed xenoantibodies in the pathomechanistic process of delayed xenograft rejection and challenge the therapeutic strategy to reduce preformed xenoantibody levels before xenotransplantation in complement-inactivated recipients.

Animals↗
PubMed1999

CD26, let it cut or cut it down.

The costimulatory properties of CD26 have been studied extensively and significant progress has been made in unravelling the complex nature of this molecule. Here, we summarize recent findings on molecular and functional characteristics of CD26. We argue that a multidisciplinary approach might reveal the molecular events underlying the role of CD26 in HIV infection and immune, inflammatory and endocrine responses.

Chemokines↗
PubMed1998

Blockade of very late antigen-4 integrin binding to fibronectin in allograft recipients. II. Treatment with connecting segment-1 peptides prevents chronic rejection by attenuating arteriosclerotic development and suppressing intragraft T cell and macrophage activation.

BACKGROUND: Chronic rejection remains the leading obstacle to long-term allograft survival. We have shown that treatment of sensitized rats with rapamycin (RPM) does not prevent progressive chronic-type cardiac allograft failure. Having documented the role of fibronectin (FN) in the allograft rejection cascade, we hypothesized that treatment with synthetic peptides that specifically block adhesive interactions between the connecting segment-1 (CS1)-binding domain of FN and alpha4beta1 integrin on circulating cells may prevent the development of chronic rejection in transplant recipients. METHODS AND RESULTS: Lewis rats were sensitized with Brown Norway skin grafts (day -7), followed by transplantation of LBNF1 hearts (day 0). Experimental animals were treated with RPM (day -7 to -1; 0.25 mg/kg/day i.p.), or RPM + CS1 peptides (day +7 to +13; 4 mg/kg/day i.v.), and euthanized at day 60. Unlike cardiac allografts in rats undergoing RPM monotherapy, those after adjunctive CS1 peptides had well preserved myocardial architecture and were free of arteriosclerotic lesions. Moreover, reverse transcription-polymerase chain reaction-based intragraft expression of transcripts for CD3, interferon-gamma, interleukin-12, monocyte chemoattractant protein-1, and transforming growth factor-beta were diminished in the CS1 group when compared with levels in the RPM group. The corresponding expression of cytokine proteins, as determined by immunoperoxidase labeling, was also depressed and correlated with decreased infiltration by T cells and macrophages. CONCLUSION: CS1 peptide-facilitated blockage of alpha4beta1-FN interactions prevents the development of chronic rejection and depresses the expression of key T cell- and macrophage-associated cytokines/chemoattractants. Hence, local synthesis of FN is an ongoing feature of, and adhesive FN-alpha4beta1 associations are critical for, the development of chronic transplant rejection.

Amino Acid Sequence↗
PubMed1998

Blockade of very late antigen-4 integrin binding to fibronectin in allograft recipients: I. Treatment with connecting segment-1 peptides prevents acute rejection by suppressing intragraft mononuclear cell accumulation, endothelial activation, and cytokine expression.

BACKGROUND: Allograft rejection is associated with infiltration of inflammatory cells and local deposition of fibronectin (FN). This study was carried out to examine the hypothesis that peptides known to specifically block adhesive interactions between the connecting segment-1 (CS1)-binding domain of FN and alpha4beta1 integrin on circulating cells may interfere with the immune cascade, which would lead to acute rejection in transplant recipients. METHODS AND RESULTS: Cardiac allografts from Lewis x Brown Norway F1 hybrids were rejected in 7+/-1 days in Lewis rats. Treatment with bioactive CS1 peptides (4 mg/kg/day i.v. for 7 days) abrogated acute rejection and prolonged cardiac allograft survival to 13+/-1 days (P<0.001). This effect correlated with decreased expression of total fibronectin and cell adhesion molecules, such as alpha4beta1, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, as well as reduced infiltration by CD4+ and CD8+ T cells at the graft site. Treatment with CS1 peptides decreased alloantigen activation, as evidenced by decreased intragraft infiltration by CD25+ cells, and diminished expression of mRNA coding for Th1 (interleukin [IL]-2, interferon-gamma)- and Th2 (IL-4, IL-5, IL-6)-type cytokines. CS1-mediated immunosuppressive effects could be reversed and acute rejection recreated after adjunctive treatment of rats with recombinant IL-2. CONCLUSION: Our data are consistent with the model in which in vivo interaction between the alpha4beta1 integrin receptor and the cell-associated CS1 motif of FN is critical for rejection cascade. The novel therapeutic approach of selectively blocking the alpha4beta1-FN activation pathway with CS1 peptides prevents acute allograft rejection by inhibiting expansion of antigen-specific T cells and inducing a transient state of cytokine-responsive anergy in the residual T-cell population.

Amino Acid Sequence↗
PubMed1997

CD28-B7 T-cell co-stimulatory blockade potentiates the effects of intrathymic immunomodulation in sensitized graft recipients.

BACKGROUND: Peripheral and central immune mechanisms contribute to the induction of tolerance in acute rejection rodent transplant models after systemic administration of CTLA4Ig and intrathymic infusion of donor alloantigen, respectively. We have investigated the effects of CTLA4Ig-induced blockade of CD28-B7 T-cell co-stimulation in conjunction with intrathymic immunomodulation on cellular and humoral immune responses leading to accelerated rejection of cardiac allografts in presensitized rats. METHODS AND RESULTS: Lewis rats were challenged with Wistar-Furth (WF) skin transplants, followed 7 days later by transplantation of WF hearts. These cardiac allografts were rejected in a fulminant manner in <24 hr. A single infusion of human CTLA4Ig (0.5 mg/rat i.v.) at the time of cardiac engraftment (day 0) did not affect accelerated rejection. Intrathymic injection of WF spleen cells (2x10[7]) at the time of skin transplantation (day -7) abrogated <24-hr rejection and extended cardiac allograft survival to 6.6+/-0.6 days. Moreover, intrathymic host immunomodulation combined with administration of human CTLA4Ig (days 0-14, every other day) extended cardiac allograft survival synergistically to 27.7+/-7.5 days, and immunomodulation combined with murine CTLA4Ig extended survival to >42.5+/-4.8 days. The prolongation of allograft survival required the blockade of both B7-1 and B7-2 ligands and was accompanied by reduction of host proliferative responses (mixed lymphocyte response) and depression of anti-donor cytotoxic T-cell generation/function (lymphocyte-mediated cytotoxicity). CTLA4Ig therapy did not affect the strong systemic IgM and IgG alloantibody response seen otherwise after intrathymic immunomodulation. CONCLUSION: CTLA4Ig enhances the effects of intrathymic donor-type cell infusion in sensitized rat recipients of cardiac allografts, indicating that "peripheral" blockade of CD28-B7 T-cell co-stimulation synergizes with the "central" immunosuppressive effects of intrathymic immunomodulation.

Abatacept↗
PubMed1997

CD28-B7 T cell costimulatory blockade by CTLA4Ig in sensitized rat recipients: induction of transplantation tolerance in association with depressed cell-mediated and humoral immune responses.

We tested the effects of blocking CD28-B7 T cell costimulation by using CTLA4Ig in an established transplantation model in which LBNF1 cardiac allografts are rejected in an accelerated manner (<36 h) by LEW rats presensitized with Brown-Norway skin grafts. Treatment with CTLA4Ig with or without donor alloantigen in the sensitization phase (between skin and cardiac engraftment) minimally delayed accelerated rejection. However, adjunctive infusion of CTLA4Ig and donor alloantigen in the effector phase (after cardiac engraftment) resulted in long term graft survival and donor-specific tolerance in 30 to 50% of the recipients. The mutant form of CTLA4Ig, which blocks B7-1 but not B7-2, was ineffective. The tolerant state was accompanied by reduction of cell-mediated (MLR/CTL) responses and depression of humoral (circulating IgM/IgG allo-Abs) alloreactivity in vivo. Hence, the binding of CD28 on T cells to both CD80 and CD86 ligands represents a crucial initial costimulatory step leading to accelerated graft rejection. CTLA4Ig-mediated early blockade of the CD28 signaling pathway combined with transfusion of donor cells in the perioperative period interrupts sensitization and may produce transplantation tolerance. This regimen inhibits T cell costimulation and activation to provide help to CD8+ cytotoxic T and B cells, perhaps, via CTLA4Ig-induced clonal anergy or deletion.

Abatacept↗
PubMed1997

Inhibition of CD26/dipeptidyl peptidase IV activity in vivo prolongs cardiac allograft survival in rat recipients.

The CD26 antigen, one of the major costimulatory molecules in T cell activation, was shown to possess dipeptidyl peptidase IV (DPP IV) activity. Previously, we demonstrated that immunosuppressed kidney transplant patients exhibit lower DPP IV serum activity as compared with healthy individuals. In the present study, we analyzed the role of CD26/DPP IV in the immune cascade triggered by organ transplantation and leading to acute rejection of cardiac allografts in rat recipients. Transplantation of hearts from (Lewis x Brown Norway)F1 donors into Lewis hosts resulted in an early (24 hr) increase in cellular CD26 expression, followed by a rise in DPP IV serum activity, which peaked at day 6, i.e., before the time of actual graft loss. Specific targeting of DPP IV activity with a novel, low-molecular-weight inhibitor of the diphenyl-phosphonate group (prodipine) abrogated acute rejection and prolonged cardiac allograft survival to 14.0+/-0.9 days (P<0.0001). Prodipine treatment prevented the early peak of cellular CD26 expression and thoroughly suppressed systemic DPP IV activity. The inhibition of DPP IV was associated with severely impaired host cytotoxic T lymphocyte responses in vitro. These results demonstrate the role of CD26/DPP IV in alloantigen-mediated immune regulation in vivo and provide the first direct evidence that CD26/DPP IV plays an important role in the mechanism of allograft rejection. The model of targeting CD26/DPP IV may reveal essential interactions on the level of costimulatory alternate T cell activation pathways, allowing a more subtle approach for more selective immunosuppression in transplant recipients.

Animals↗
PubMed1992

[Indications for aboral subtotal resection].

Aboral gastric resections for gastric cancer are performed in 20%-40% of cases at German university hospitals. This type of resection can only be carried out if an ample oral safety margin is given. The margin should be at least 10 cm in the case of diffuse carcinoma, and no less than 6 cm in intestinal-type carcinoma. Thus, aboral subtotal resection is confined to smaller tumors, preferably those located in the antrum of the stomach. Lymph node dissection can and should be carried out in the case of subtotal resection. Aboral subtotal resection represents an adequate form of treatment, complying with the necessary oncological standards if the appropriate safety margin is chosen.

Follow-Up Studies↗
PubMed1990

Effects of Escherichia coli hemolysin on human monocytes. Cytocidal action and stimulation of interleukin 1 release.

This study reports on the potent cytocidal and interleukin-1 releasing properties of Escherichia coli hemolysin (ECH) on human monocytes. Nanomolar concentrations of purified ECH (250-2,000 ng/ml) caused rapid and irreversible depletion of cellular ATP to levels below 20% of controls within 60 min. Subcytocidal doses (10-200 ng/ml) of ECH induced rapid release within 60-120 min of large amounts of interleukin 1 beta (IL-1 beta) from cultured monocytes. IL-1 beta release occurred in the presence of actinomycin D and cycloheximide, and was thus probably due to processing and export of intracellular IL-1 beta precursor. Incubation of toxin-producing E. coli at ratios of only 0.3-3 colony-forming units per monocyte evoked approximately 50% depletion of total cellular ATP within 90 min. Toxin producers also stimulated synthesis and release of large amounts of interleukin 1, but not of tumor necrosis factor within the same time span. In contrast, non-toxin producers caused neither cell death nor rapid interleukin 1 release. Stimulation of rapid interleukin 1 release coupled with potent cytocidal effects on cells of monocytic origin may represent pathogenetically significant events incurred by bacterial strains that produce ECH and related cytolysins.

Adenosine Triphosphate↗