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Biomedical subjects

A Zeevi

Publications and source records attributed to A Zeevi.

At least 91 records · Page 5Linked to original sources
PubMed1995

Obliterative bronchiolitis after lung and heart-lung transplantation. An analysis of risk factors and management.

With a prevalence of 34% (55/162 at-risk recipients) and a mortality of 25% (14/55 affected recipients), obliterative bronchiolitis is the most significant long-term complication after pulmonary transplantation. Because of its importance, we examined donor-recipient characteristics and antecedent clinical events to identify factors associated with development of obliterative bronchiolitis, which might be eliminated or modified to decrease its prevalence. We also compared treatment outcome between recipients whose diagnosis was made early by surveillance transbronchial lung biopsy before symptoms or decline in pulmonary function were present versus recipients whose diagnosis was made later when symptoms or declines in pulmonary function were present. Postoperative airway ischemia, an episode of moderate or severe acute rejection (grade III/IV), three or more episodes of histologic grade II (or greater) acute rejection, and cytomegalovirus disease were risk factors for development of obliterative bronchiolitis. Recipients with obliterative bronchiolitis detected in the preclinical stage were significantly more likely to be in remission than recipients who had clinical disease at the time of diagnosis: 81% (13/15) versus 33% (13/40); p < 0.05). These results indicate that acute rejection is the most significant risk factor for development of obliterative bronchiolitis and that obliterative bronchiolitis responds to treatment with augmented immunosuppression when it is detected early by surveillance transbronchial biopsy.

Adolescent↗
PubMed1995

Efficacy of inhaled cyclosporine in lung transplant recipients with refractory rejection: correlation of intragraft cytokine gene expression with pulmonary function and histologic characteristics.

BACKGROUND: Refractory rejection is a major cause of morbidity and death among lung transplant recipients. Traditional rescue therapies have proved only modestly successful. We recently demonstrated the safety of inhaled cyclosporine for patients with end-stage chronic rejection; this trial was extended to patients with refractory acute rejection. The present study was to determine whether effective inhaled cyclosporine therapy was correlated with suppression of cytokine gene expression. METHODS: Twelve lung transplant recipients were studied. Maintenance therapy, cyclosporine or FK 506, azathioprine, and prednisone, was continued, and inhaled cyclosporine at a dose of 300 mg/day was added. Pulmonary function testing and histologic characteristics from transbronchial biopsy specimens were used to assess efficacy of therapy. Bronchoalveolar lavage (BAL) and peripheral blood cells were analyzed for the presence of messenger RNA by using 32P-labeled primers of cytokines interleukin-2 (IL-2), IL-6, IL-10, and interferon-gamma (gamma) via reverse transcriptase-polymerase chain reaction. RESULTS: Nine of 12 patients (five with acute rejection, four with chronic rejection) exhibited histologic resolution of rejection within 3 months of inhaled cyclosporine therapy. Pulmonary function (forced expiratory volume in 1 second) improved from pretherapy levels in the patients with acute rejection (p < 0.05). All of the nine histologic responders exhibited 4- to 150-fold decreases (p < 0.05) in IL-6 and interferon-gamma messenger RNA levels in the BAL, whereas the three patients who failed exhibited persistent or increased cytokine profiles. IL-2 and IL-10 in BAL and peripheral blood lymphocyte cytokines were not informative. CONCLUSIONS: These results indicate that inhaled cyclosporine is effective therapy for refractory pulmonary rejection and that its mechanism of action is associated with suppression of proinflammatory cytokines IL-6 and interferon-gamma within the allograft.

Administration, Inhalation↗
PubMed1995

Mode of action of tacrolimus (FK506): molecular and cellular mechanisms.

Tacrolimus, formerly known as FK506, is a macrolide antibiotic with immunosuppressive properties. Although structurally unrelated to cyclosporin A (CsA), its mode of action is similar. It exerts its effects principally through impairment of gene expression in target cells. Tacrolimus bonds to an immunophilin, FK506 binding protein (FKBP). This complex inhibits calcineurin phosphatase. The drug inhibits calcium-dependent events, such as interleukin-2 gene transcription, nitric oxide synthase activation, cell degranulation, and apoptosis. Tacrolimus also potentiates the actions of glucocorticoids and progesterone by binding to FKBPs contained within the hormone receptor complex, preventing degradation. The agent may enhance expression of the transforming growth factor beta-1 gene in a fashion analogous to that demonstrated for CsA. T cell proliferation in response to ligation of the T cell receptor is inhibited by tacrolimus. Type 1 T helper cells appear to be preferentially suppressed compared with type 2 T helper cells. T cell-mediated cytotoxicity is impaired. B cell growth and antibody production are affected indirectly by the suppression of T cell-derived growth factors necessary for these functions. Antigen presentation appears to be spared. The molecular events affected by tacrolimus continue to be discovered.

Gene Expression Regulation↗
PubMed1995

Cytokine induction during cardiac surgery: analysis of TNF-alpha expression pre- and postcardiopulmonary bypass.

Cytokines are soluble mediators that possess both intra- and intercellular signaling properties. Their function has been investigated most thoroughly in the context of immune reactions. Cytokines, however, form an important component of the inflammatory response to trauma and are found in elevated concentrations following cardiopulmonary bypass (CPB). We were, therefore, interested in studying mRNA expression for the cytokine tumor necrosis factor alpha (TNF-alpha) in patients undergoing cardiac surgery. White cells isolated from the circulation of seven patients before and after CPB were assayed for the expression of mRNA with TNF-alpha specific primers using the polymerase chain reaction. Message for TNF-alpha was found in all patients, with the highest values demonstrated in patients whose CPB times exceeded 1 1/2 hours. Enhanced message expression was seen as early as 1 hour after the start of CPB. Genes responsible for cytokine (TNF-alpha) expression and production are activated during cardiac surgery.

Base Sequence↗
PubMed1995

Phenotypic and functional characteristics of colonic lymphocytes isolated from patients with primary sclerosing cholangitis and inflammatory bowel disease.

Because primary sclerosing cholangitis (PSC) frequently is associated with inflammatory bowel disease, the phenotypic and functional characteristics of lymphocytes isolated from colonic mucosa were studied in patients with primary sclerosing cholangitis (PSC), patients with ulcerative colitis and patients with other colonic and hepatic disorders. To accomplish this, lymphocytes isolated from colonic biopsies obtained at the time of colonoscopy were expanded in vitro in the presence of interleukin 2 (IL2). Cell propagation was similar in patients with PSC with or without associated inflammatory bowel disease but was diminished significantly when compared to results obtained in patients with ulcerative colitis not associated with PSC. The CD4:CD8 ratio of the propagated lymphocytes was increased in patients with PSC compared to controls. The Leu 19+ subset of cells was also increased in PSC patients. In patients with inflammatory bowel disease, increased cytotoxicity was noted at low effector to target cell ratios with SK-HEP (hepatocellular carcinoma) but not RPMI 7451 (cholangiocarcinoma) targets. No differences between PSC patients and controls were observed for NK sensitive and NK resistant targets. Based upon these studies it can be concluded that: 1) expansion of lymphocytes obtained from endoscopic colonic biopsies using recombinant IL2 represents an alternative method by which intestinal lymphocytes can be studied; 2) natural killer cells are increased in the colonic mucosa of patients with primary sclerosing cholangitis; 3) colonic cytotoxic T lymphocytes may be more active in patients with chronic liver disease and particularly those with associated inflammatory bowel disease.

Adult↗
PubMed1995

Immunologic consequences of transplantation.

With current immunosuppressive regimens, rejection is common after lung transplantation. Acute rejection is usually easily reversible with therapy, but chronic rejection often responds poorly and is the leading cause of late morbidity and mortality. Although the pathogenesis of chronic rejection is not fully understood and might be different from ACR, the studies summarized in this review support the concept that alloimmune responses are of fundamental importance. Acute rejection and infection, particularly with CMV, appear to promote changes within the allograft that increase the risk of chronic rejection. Although the progression of OB in some patients might be arrested with immunosuppression, a large percentage of patients with OB suffer from a continuous loss of lung function. Improvement in the long-term outcome of lung transplant recipients will require both better immunosuppressive agent and more specific therapy such as induction of donor-specific tolerance.

Biopsy↗
PubMed1994

Bone marrow augmentation of donor-cell chimerism in kidney, liver, heart, and pancreas islet transplantation.

We have previously postulated that donor cell chimerism in organ transplantation is needed to attain a tolerant state. Here we show that donor cell chimerism can be augmented in organ recipients if they are infused perioperatively with 3 x 10(8) per kg of unmodified donor bone marrow cells and are kept on a conventional immunosuppressive regimen of tacrolimus (FK506) and prednisolone. 36 patients took part, of whom the first 18 patients have good transplanted kidney (n = 10), liver (n = 7), and heart (n = 7) function when followed up between 4 and 16 months. All patients are well. We found persistent multilineage leucocyte chimerism in blood of 17 recipients by flow cytometry and PCR techniques to detect donor alleles or Y chromosomes in female recipients of male organs. The use of the 5-antigben HLA matched same sex donor precluded detection of chimerism in one patient.

Adult↗
PubMed1994

Morphologic and immunophenotypic characterization of a cell line derived from liver tissue with Epstein-Barr virus associated post-transplant lymphoproliferative disease.

A B-cell line was established from the liver of an 11-yr-old boy with Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disease (PTLD). The cells were morphologically heterogenous, CD10 (CALLA) negative, and expressed several B-cell antigens, including CD23, in a manner reminiscent of lymphoblastoid cell lines (LCLs) reported in the literature. However, the cells also showed expression of the CD77 antigen, carried a 14q32+ chromosomal anomaly, and showed IgM-kappa immunoglobulin isotype restriction immediately after their outgrowth in culture. These latter properties are typically associated with Burkitt's lymphoma cell lines rather than LCLs. Aberrant expression of the L60 antigen on these B-cells was found as additional evidence of altered growth regulation in these cells. EBV infection was demonstrated by the abundant expression of EBNA-2 and LMP viral antigens in culture. The cell line described should be useful in planning in vitro experiments designed to understand the factors that modulate the growth of PTLD in vivo.

Antigens, CD↗
PubMed1994

Early tolerance in pediatric liver allograft recipients.

The authors report on six pediatric liver transplant recipients for whom allograft tolerance occurred shortly after transplantation (ie, less than 1.5 years). All the patients had associated life-threatening viral complications. They are currently immunocompetent. The tolerant state may be related to the development of a TH2 cytokine pattern.

Female↗
PubMed1994

Mixed allogeneic chimerism in lung allograft recipients.

Microchimerism in lung allograft recipients was studied in the autopsies of nine female recipients of male lung grafts who had survived for more than 1 month after transplantation. Using a Y chromosome-specific probe tissues were studied for the presence of donor cells that had migrated beyond the graft itself. They were quantitated by cell counting to give absolute numbers of cells per organ volume. While donor cells were disseminated throughout the body, their numbers were small. These absolute numbers should be studied in a larger group of recipients to determine if they correlate with prognosis and the development of bronchiolitis obliterans.

Adult↗
PubMed1994

Renal transplantation at the University of Pittsburgh: the impact of FK506.

1. In an unselected adult renal transplant population, FK506 as the primary immunosuppressive agent yielded one- and 2-year actuarial patient survival rates of 95% and 93% and one- and 2-year actuarial graft survival rates of 89% and 83%, respectively. Forty-nine percent of successfully transplanted patients were weaned off steroids. 2. In pediatric renal transplant patients, FK506 has been associated with 100% one- and 3-year actuarial patient survival rates and 98% and 85% one- and 3-year actuarial graft survival rates, respectively. Sixty-two percent of successfully transplanted patients were taken off prednisone, with dramatic improvements in height. 3. FK506 has been used successfully in rescuing 70-74% of adult or pediatric renal transplant patients with an acute rejection that failed conventional therapy. 4. Kidney/bone marrow transplantation under FK506 therapy has been successfully performed without graft-versus-host disease and with routine augmentation of chimerism. 5. The side effects of FK506 included nephrotoxicity, neurotoxicity, and diabetogenicity; they were comparable to those seen with CsA. 6. FK506 is an important new addition to the immunosuppressive armamentarium in renal transplant patients.

Actuarial Analysis↗
PubMed1994

Human leukocyte antigen-class II-positive human corneal epithelial cells activate allogeneic T cells.

PURPOSE: To achieve a better understanding of the mechanism of corneal immune diseases, including corneal allograft rejection, the authors examined the potential of human corneal epithelial (HCE) cells to activate allogeneic T lymphocytes. METHODS: The mixed lymphocyte-HCE cell reaction (MLCER) was performed as follows: HCE cells from primary cultures, with or without treatment with interferon-gamma (IFN-gamma), were treated with mitomycin C and then mixed with peripheral blood lymphocytes (PBL) from normal volunteers. Triplicate cultures were incubated for 7 days. Interleukin-1-alpha (IL-1-alpha) was added to some cultures to examine its effect on MLCER: The lymphocyte responses were measured by 3H-thymidine uptake for the last 18 hours of incubation in MLCER: RESULTS: IFN-gamma-treated, HLA-class-II-bearing HCE cells stimulated allogenic lymphocytes, whereas IFN-gamma nontreated, class-II-negative HCE cells did not. The stimulation by IFN-gamma-treated HCE cells was blocked by anti-HLA class II monoclonal antibody. In addition, exogenous IL-1-alpha reduced the lymphocyte response in MLCER: This effort was inhibited by indomethacin. CONCLUSIONS: This study demonstrates that HLA-class-II-bearing HCE cells can activate allogeneic PBL by a major histocompatibility complex class II-dependent mechanism. In addition, HCE cells may regulate immune reactions, probably through prostaglandin production caused by IL-1.

Antigen-Presenting Cells↗