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A Zeevi

Publications and source records attributed to A Zeevi.

At least 145 records · Page 8Linked to original sources
PubMed1991

Propagation and characterization of lymphocytes from transplant biopsies.

This review shows that the propagation and characterization of lymphocytes from various solid organ allografts leads to a better understanding of cellular transplant immunity. Clinically relevant information generated by many studies offers opportunities for better management of transplant patients for cellular rejection. These studies provide experimental support of the importance of various class I and class II HLA antigens in cellular rejection, and frequently the population of infiltrating alloreactive T cells is clonally restricted. Evidence has also accumulated that class I-specific CD8+ cells often appear first in the allograft undergoing early rejection. Allograft derived lymphocytes can also be used in in vitro models to study interactions with vascular endothelium and other targets of cellular rejection. Studies on biopsy propagated cells have also increased our understanding of chronic rejection and intragraft tolerance. Nevertheless, many unanswered questions remain which need to be addressed in future studies. This particularly applies to the mechanism of intragraft T-cell clonality and the characterization of cells mediating chronic rejection or transplant tolerance. A major area of investigation needed over the next few years should address the role of cytokines in the complex interactions between cells mediating the inflammatory process during allograft rejection and the mechanisms of donor tissue injury. This can be done by determining cytokine release by allograft derived cell cultures and by applying molecular techniques to measure in situ production of cytokines in allograft tissue specimens. Given the plethora of cytokines identified so far (the list is still growing), it would be difficult to determine the functional role of individual cytokines in the inflammatory process. Most cytokines have been ascribed multiple functions and for several, their activity requires a synergism with other cytokines or immune modulators. The biological significance of cytokine function must be assessed at different phases during the cascade of effector mechanisms leading to cellular rejection. The first phase pertains to the interactions between lymphocytes and the vascular endothelium. Major events include lymphocyte adhesion to the EC, specific allorecognition, and cellular activation. A variety of cytokines have been identified which upregulate the expression of adhesion molecules and HLA alloantigens at the cell surface. This augments the activated state of the adhering T cells and also triggers the endothelium to attract other leukocytes and permit diapedesis of adhering cells. Although at least four systems of interrelated adhesion receptor-ligand combinations have been shown to influence lymphocyte-endothelium interactions, it is unclear how much each contributes to the process of lymphocyte infiltration through the vascular endothelial barrier.(ABSTRACT TRUNCATED AT 400 WORDS)

Biopsy↗
PubMed1990

Increased lymphocyte adherence to human arterial endothelial cell monolayers in the context of allorecognition.

The interactions of alloreactive T lymphocytes with the vascular endothelium were studied in an in vitro model of lymphocyte adherence to cultured human arterial endothelial cell (HAEC) monolayers. Donor-primed lymphocytes (DPL) were shown to have significantly greater adherence to donor HAEC than were third-party primed lymphocytes. Limiting dilution analysis of adherent DPL showed an enrichment of donor-reactive lymphocytes compared with nonadherent DPL. This study examines the allospecific nature of this increased lymphocyte adherence. HAEC constitutively express class I HLA Ag and can be induced by IFN-gamma to express class II Ag. DPL adherence to class I+ HAEC was inhibited only in the presence of mAb directed against class I Ag. DPL adherence to class I+ and class II+ HAEC was inhibited in the presence of mAb directed against class I and class II Ag. Class I- and class II-specific adherence was also shown to involve CD8 and CD4 molecules, respectively, whereas lymphocyte function-associated Ag do not appear to play a major role in long term alloreactive lymphocyte adherence to HAEC. These findings suggest that alloreactive lymphocyte adherence to HAEC is mediated by two mechanisms. One is based on allorecognition, primarily of HLA Ag, and the other is related to presumably non-Ag-specific interactions between activated lymphocytes and the vascular endothelium. The studies presented provide evidence to suggest that HLA-specific lymphocyte adherence to endothelium may significantly contribute to the development of alloreactive lymphocyte infiltrates within the allograft.

Antibodies, Monoclonal↗
PubMed1990

Life in the allogeneic environment after lung transplantation.

Because infection and rejection are the principal complications of any transplant procedure and because the alveolar macrophage is crucial to the defense of the lung from infection and may play a role in lung allograft rejection, we have begun to assess functions of this cell that are thought to be important in lung defense from infection and in transplant immunity. Antimicrobial functions include chemotaxis, which is a mechanism for recruiting macrophages to sites of inflammation and phagocytosis, and intracellular killing of microorganisms. As an accessory cell, the alveolar macrophage is necessary for an effective immune response to develop against either microorganisms or transplantation antigens. Our results indicate that the chemotactic, phagocytic but not the killing capability of alveolar macrophages from lung recipients is impaired. Alveolar macrophages and blood monocytes from lung recipients are also significantly impaired in their support for mitogen and antigen presentation to lymphocytes. Thus, the generation of an effective immune response to a microorganism may be impaired. Alveolar macrophages from lung recipients, however, function as well as those from normal subjects in stimulating lymphocyte proliferation in response to donor antigens (primed lymphocyte test) or unrelated allogeneic antigens (mixed lymphocyte reaction), while their respective blood monocytes function poorly in this regard. Our conclusions are that the antimicrobial functions of the alveolar macrophages are impaired after lung transplantation and this may be one mechanism to explain the unusual susceptibility of the lung allograft to infection. Those functions related to transplant immunity, however, are preserved and indicate that the alveolar macrophage may play a role in allograft rejection.

Adolescent↗
PubMed1990

Donor-specific cytotoxicity testing: an advance in detecting pulmonary allograft rejection.

Ten beagle dogs underwent left unilateral lung transplantation and were treated with cyclosporine and azathioprine. After three days, cyclosporine administration was discontinued and azathioprine administration was maintained at a suboptimal dose to allow a graded response to the pulmonary allograft. Dogs were monitored by chest roentgenogram, bronchoalveolar lavage (BAL), and sampling of peripheral blood lymphocytes at weekly intervals. Open lung biopsies also were performed at weekly intervals in 5 of the dogs. Lymphocytes from the BAL and peripheral blood and those grown in culture from open and transbronchial biopsy specimens were tested for donor-specific cytotoxicity (DSC) by testing their responsiveness to lymphocytes from their donor. Rejection was confirmed in all animals. Donor-specific cytotoxicity became detectable in all animals in either the BAL fluid or biopsy specimens. An abnormal chest roentgenogram developed in 9 dogs, but not until after DSC was detected in the BAL in 7. In the open biopsy specimens tested for DSC, all exhibited DSC synchronous with the first changes noted on chest roentgenogram. Donor-specific cytotoxicity was sensitive for detecting rejection in 8 of 9 dogs in the BAL and in 5 of 5 dogs in the open biopsy specimens. Based on these results, 3 additional dogs were maintained on cyclosporine. Two of these dogs did not reject their transplants and had no evidence of DSC. We conclude that donor-specific functional assays provide an advance over less sensitive clinical techniques.

Animals↗
PubMed1990

Propagation of infiltrating lymphocytes and graft coronary disease in cardiac transplant recipients.

The pattern of lymphocyte growth from endomyocardial biopsies in 55 heart transplant recipients was shown to be correlated with the subsequent development of graft coronary disease. Persistent lymphocyte growth was observed in 39 patients, and 15 of these growers (or 41%) developed graft coronary disease. In contrast, only 1 of 15 patients (or 6%) with nongrower biopsies showed subsequent graft coronary disease. Thus, biopsy growth was associated with a higher incidence of subsequent GCD (p = 0.02). A comparison between the group of 15 growers with subsequent graft coronary disease and the 24 growers without subsequent graft coronary disease did not show any differences with respect to patient age, presence of coronary artery disease in the native heart, biopsy histology, donor alloreactivity of biopsy grown lymphocytes, and immunosuppressive drug regimen. On the other hand, the number of treated rejection episodes was significantly lower in the grower group with subsequent graft coronary disease (p = 0.04). These data support the concept that graft coronary disease may involve rejection and that more immunosuppression may lower its incidence. This concept is strengthened by findings showing that alloreactive T cells can be propagated from coronary arteries of cardiac allografts with graft coronary disease.

Biopsy↗
PubMed1990

Propagation and characterization of lymphocytes infiltrating livers of patients with primary biliary cirrhosis and autoimmune hepatitis.

Lymphocytes were propagated with interleukin 2 from liver tissue removed at transplantation from patients with primary biliary cirrhosis or autoimmune chronic active hepatitis. Phenotypic analysis of the cultured lymphocytes as well as the infiltrating cells in situ indicated that the culture technique did not select for a particular phenotype. Eight cultures were tested for cell-mediated lympholysis activity against a bile duct tumor line as well as a hepatocellular carcinoma line, but no specific killing was seen. In addition, no natural killer activity was detected. However, the lymphocyte cultures were able to kill the targets in a lectin-dependent cytotoxicity assay, indicating their cytolytic effector activity. Preliminary studies have demonstrated that lymphocytes extracted from hepatic tissue and hilar lymph nodes from a patient with primary biliary cirrhosis proliferated in response to autologous biliary epithelial cells. These methods might be useful in studying the pathogenesis of primary biliary cirrhosis and other liver diseases with autoimmune features.

Adult↗
PubMed1990

Propagation of lymphocytes infiltrating human liver allografts. Correlation with histologic diagnosis of rejection.

In this study, we have investigated whether lymphocyte growth from 196 liver transplant biopsies is correlated with the histologic diagnosis of graft rejection. One fragment of each biopsy was cultured in IL-2 to expand activated T cells, and the remainder of the biopsy was analyzed histologically. A significantly higher number of biopsies with rejection grew lymphocytes when compared to those biopsies showing no evidence of rejection (P = 0.009). Lower growth rates were observed with biopsies taken from patients on OKT3 therapy (12% vs. 29% from patients not on OKT3), so when the data were reanalyzed after omitting those biopsies we observed an even stronger correlation of growth with rejection (P = 0.001). In spite of the fact that hepatitis biopsies are also infiltrated by lymphoid cells, the frequency of lymphocyte growth (16%) was similar to that observed for the biopsies with no rejection or hepatitis (19%) and much lower than for biopsies with rejection (42%). Over all, 82% of the cultures tested were positive for donor PLT reactivity, suggesting that current culture conditions favor alloreactive lymphocyte proliferation. The size of the biopsy cultured was found to be an important factor in the propagation of biopsy-infiltrating lymphocytes. Only 25% of smaller (less than 3 mm long) biopsies with rejection grew lymphocytes compared to 91% of the large-sized biopsies (greater than 5 mm long). It is likely that culture techniques will need to be modified in order to successfully propagate infiltrating lymphocytes that recognize antigens other than alloantigens.

Antibodies, Monoclonal↗
PubMed1990

Proliferative responses of bronchoalveolar lavage lymphocytes from heart-lung transplant patients.

Donor-specific alloreactivity of bronchoalveolar lavage (BAL) lymphocytes was evaluated in the immunologic monitoring of lung transplant patients. The study dealt with 161 BAL performed on 28 transplant recipients. Unseparated BAL cells, separated BAL lymphocytes, and PBL were tested for donor-specific proliferative responses in 3-day primed lymphocyte testing (PLT), and for nonspecific proliferative responsiveness to exogenous IL-2. The proliferation data were analyzed for correlation with the status of the lung allograft assessed clinically, histologically, and by pulmonary function testing. Positive PLT responses of BAL lymphocytes were observed in 20 of 22 acute rejection episodes (91%) and in 24 of 35 cases (69%) when chronic rejection was diagnosed. During clinical quiescence donor-specific proliferative activity was demonstrated in only 4 of 35 cases (11%). Thus, acute rejection and chronic rejection correlated significantly (P less than 0.001) with donor-specific PLT reactivity of BAL lymphocytes. Though significant association with rejection was observed for the alloreactivity of unseparated BAL cells and PBL, the sensitivity of the PLT test with these cells was significantly lower than that with BAL lymphocytes. Similarly, the IL-2 proliferative activity of BAL lymphocytes was significantly increased during acute and chronic rejection. However, this test had lower sensitivity and specificity than did the donor-specific PLT. These findings suggest the usefulness of the donor-specific PLT of BAL lymphocytes as a reliable method for monitoring pulmonary rejection.

Adolescent↗
PubMed1990

HLA-class II antigen expression in human heart-lung allografts.

Long-term survival in heart-lung transplantation has ben hindered by the development of bronchiolitis obliterans (OB), which is believed to be a manifestation of chronic rejection of the lung. Since HLA-class II antigens are involved in the rejection response, the distribution of the class II products HLA-DR, HLA-DQ, and HLA-DP were studied in normal lung, and in transplanted lung with and without OB, utilizing frozen-section immunohistochemical techniques. All three allelic products are usually expressed on the epithelial, endothelial, and mesenchymal components of the lung. Sequential transbronchial biopsies from 4 recipients before and concurrent with the diagnosis of OB were stained with serial dilutions of monoclonal antibodies to assess the level of expression of the above class II products. Increased levels of HLA-DR and HLA-DP antigens may be seen on the bronchial and bronchiolar epithelium during OB, but the changes are subtle and complicated by many other variables. Additional studies are needed to confirm these preliminary results.

Bronchiolitis Obliterans↗
PubMed1989

Propagation of alloreactive lymphocytes from histologically negative endomyocardial biopsies from heart transplant patients. Association with subsequent histological evidence of allograft rejection.

Endomyocardial biopsies from heart transplant patients were cultured in vitro in the presence of Interleukin-2 and irradiated feeder cells to propagate graft-infiltrating lymphocytes. A correlation was seen between the frequency of lymphocyte growth and the degree of cellular infiltration of the biopsies. In this study, 43 of 113 (38%) histologically negative biopsies obtained from 55 patients during the first month post-transplant yielded lymphocyte cultures. The cumulative incidence of subsequent histological rejection was considerably higher in patients with such "grower" biopsies than in patients with "nongrower" biopsies. In the grower group, we were able to obtain data on alloreactivity of 32 lymphocyte cultures assayed by primed lymphocyte testing (PLT). The presence of donor-specific PLT reactivity in the cultured lymphocytes was associated with an additional risk for subsequent histological rejection. These findings suggest that the in vitro culturing of histologically negative endomyocardial biopsies will identify patients at increased risk for developing heart transplant rejection.

Biopsy↗