Defective T suppressor-inducer cell function in human immune deficiency virus-seropositive hemophilia patients

In human immune deficiency virus (HIV)-seropositive hemophilia patients, a low number of CD4 + lymphocytes is found, as well as a low CD4+/CD8+ ratio. In previous studies, it has been shown that antigen- specific T-helper cell (CD4+) function was present and no excessive antigen-specific T-suppressor cell (CD8+) function could be demonstrated. In this report, we studied another activity of CD4+ cells, namely the capacity to induce T-suppressor cell activity. The results clearly show a selective dysfunction of CD4+ suppressor-inducer (Tsi) cell function. Since these HIV-seropositive hemophilia patients showed the presence of activated B cells in the peripheral circulation refractory to antigen-specific T-helper cell signals and secreting specific antibodies spontaneously, we raised the hypothesis that the activated B cells in the patients activate the Tsi cells in vivo. This constant activation leads to a functional exhaustion of the Tsi cell pool.     

Recovery of T cell subsets after autologous bone marrow transplantation is mainly due to proliferation of mature T cells in the graft

In 22 patients with malignancies, treated with high-dose chemoradiotherapy and autologous bone marrow transplantation (BMT), peripheral blood T cell subsets and functions were studied. In ten cytomegalovirus (CMV)-negative patients, CD4+ and CD8+ T cells (representing T cells of the helper/inducer phenotype and T cells of the suppressor/cytotoxic phenotype, respectively), recovered slowly and simultaneously. In 12 CMV-positive patients, however, CD8+ T cells recovered more rapidly than CD4+ T cells and rose to increased counts. No T cells with an immature phenotype (CD1+, OKT6+) were observed. Lymphocyte stimulation by herpes simplex virus infected fibroblasts (and by CMV-infected fibroblasts in CMV-positive patients) in contrast remained high and even increased after BMT in both groups. These data indicate that T cell recovery after autologous BMT is mainly due to proliferation of mature T cells present in the BM graft and not to generation of new T cells from T cell precursors.     

Correlation of P-glycoprotein expression and function in childhood acute leukemia: a children's cancer group study

Clinical drug resistance may be attributed to the simultaneous selection and expression of genes modulating the uptake and metabolism of chemotherapeutic agents. P-glycoprotein (P-gp) functions as a membrane-associated drug efflux pump whose increased expression results in resistance to anthracyclines, epipodophyllotoxins, vinca alkaloids, and some alkylating agents. This type of resistance occurs as both de novo and acquired resistance to therapy for leukemia. We have studied P- gp expression and function in childhood acute leukemias by developing a series of doxorubicin- and vincristine-selected CEM, T-cell lymphoblastoid cell lines that recapitulate the low levels of expression and resistance seen clinically. These cell lines have been used to develop flow cytometric assays for the semiquantitative measurements of P-gp expression with the MRK16 monoclonal antibody and P-gp function using the enhanced retention of rhodamine 123 in the presence of verapamil, a resistance modulator. Kolmogorov-Smirnov statistics, represented by the D measurement, are used to determine the difference in level of P-gp expression by comparing MRK16 staining to an IgG2a isotype control. When D is > 0.09, there is an excellent correlation (R = 0.82) between P-gp expression and function. The evaluation of 107 bone marrow specimens from 84 children with lymphoblastic or myelogenous leukemia showed a statistically significant (P = .004) increase in P-gp function at relapse. P-gp expression at relapse, however, approached but did not reach a significant level (P = .097). Using this methodology, we can identify patients with levels of P-gp expression and function that we can define clinically, as well as children with discordant multidrug resistance phenotypes. This study supports the role of P-gp-mediated drug resistance in childhood leukemia and confirms that P-gp expression and function are measurable in their leukemic blasts. These assays provide the means for the in vitro testing of resistance modulators and the monitoring of in vivo response to treatment with these agents.     

Chemoattractant-induced changes in surface expression and redistribution of a functional ligand for P-selectin on neutrophils

Adhesion between platelets and neutrophils is mediated through the interaction of P-selectin on activated platelets with a carbohydrate- containing structure on neutrophils, and occurs under both static and shear conditions. Recent studies using flow chambers have shown that neutrophils become activated after binding to surface-adherent platelets expressing P-selectin. The objective of the present study was to investigate the effect of such activation on the interactions of platelet P-selectin with its ligand on neutrophils. Flow cytometric analyses using P-selectin chimeras revealed that activation induced a rapid and marked reduction in chimera binding, with levels of binding decreased by 71% after 15 minutes of stimulation with the chemotactic agent, FMLP. Using a visual assay of platelet-neutrophil rosetting, we showed that the P-selectin ligand was translocated and clustered at the uropod of neutrophils following the shape changes and polarization induced by chemotactic stimulation. Activated neutrophils bound to surface-adherent platelets also displayed the clustering of P-selectin ligand at the uropod, and these neutrophils detached from the platelets when a shear stress (2 dynes/cm2) was applied through the adhesion chamber. These results indicate that chemotactic stimulation of neutrophils induces changes in the surface expression and distribution of a biologically relevant ligand for P-selectin, and that these changes might influence the adhesive interactions occurring between neutrophils and activated platelets.     

Inhibition of endotoxin-induced activation of the coagulation and fibrinolytic pathways using a recombinant endotoxin-binding protein (rBPI23)

A recombinant endotoxin-neutralizing protein, rBPI23, was shown to partially prevent endotoxin-induced activation of the fibrinolytic and coagulation systems in experimental endotoxemia in humans. In a placebo- controlled, blinded crossover study, eight volunteers were challenged twice with an intravenous bolus injection of endotoxin (40 EU/kg of body weight) and concurrently received either rBPI23 (1 mg/kg) or placebo (human serum albumin, 0.2 mg/kg). rBPI23 treatment significantly lowered the endotoxin-induced fibrinolytic response, ie, reduced the release of tissue-type plasminogen activator, urokinase- type plasminogen activator, plasminogen activator inhibitor antigen, and complex formation of plasmin alpha 2-antiplasmin (P = .0078 for each). Plasminogen activator inhibitor activity was also reduced, but not significantly according to the Hochberg method (P = .0304). The endotoxin-induced activation of the procoagulant state as reflected by increase in F1 + 2 fragments and TAT complexes was blunted by rBPI23 infusion (P = .0391 [not significant according to the Hochberg method] and .0078, respectively). These results indicate that rBPI23 is capable of reducing both the activation of the fibrinolytic and the coagulation systems after low-dose endotoxin infusion in humans.     

Assay of pig growth hormone preparations for metabolic activities in the rat and in man.

The possible somatotropic effect in man of porcine growth hormone (pGH) and its plasmin digest has not been comprehensively studied before. For this purpose, pGH was digested with rat or human plasmin; acrylamide gel electrophoresis showed less than 10% native pGH remaining in the digests. Native pGH and the 2 types of plasmin digest possessed similar GH potency, as measured by the weight gain assay in the hypophysectomized rat: 1-2 IU/mg. In 7 GH-deficient children and 3 adults with myotonic dystrophy, we measured the capacity of human GH (hGH), pGH, and pGH plasmin digests to cause: a) the retention of N, P, K, Na, and Cl; b) a rise in plasma free fatty acids; c) a fall in plasma alpha-amino NL d) impaired glucose tolerance; and e) hyperinsulinemia. Human GH was active in all respects at minimal effective dosages of .0168 to 0.168 IU/kg BW(3/4) per day. The pGH preparations had no detectable effect at 0.532 I.U./kg BW(3/4)/day. The data show that in man pGH and its plasmin digests possess less than 1/30, less than 1/10, and less than 1/3 the anabolic, adipokinetic, and diabetogenic potencies of hGH, respectively.     

Is chronic graft rejection the reason for degenerative changes in allogeneic and xenogeneic heart valve prostheses: immunohistochemical evaluation of inflammatory factors

OBJECTIVES: After a period of 5 to 10 years, biological heart valve prostheses undergo degenerative processes, which finally lead to dysfunction and complete destruction. Although many efforts have been made to identify underlying mechanisms, many questions remain unanswered. Here we evaluate immunological factors and their potential role in biological heart valve destruction. PATIENTS AND METHODS: Allogeneic (n=10) and xenogeneic (n=3) aortic valvular prostheses, as well as aortic valves retrieved from transplanted human hearts, which had to be replaced because of chronic graft rejection (n=4) were analyzed. Aortic valves from human donor hearts (native) (n=4), which were considered not transplantable served as controls. Endothelial expression patterns of the following adhesion molecules were analyzed by immunohistochemistry: selectin family: ELAM-1, CD62, integrin family: VLA-1, -2, -3, -4, -5, and -6, immunoglobulin supergene family: PECAM-1, ICAM-1, and -2, and class I heavy chain proteins, complementary adhesion molecules: CD34, CD44 and the von Willebrand factor. RESULTS: ELAM-1, ICAM-1 and -2, CD34, CD44 and class I heavy chain proteins, all molecules which play significant roles during inflammatory processes, showed stronger expression patterns in allogeneic and xenogeneic aortic heart valve prostheses compared to native or chronically rejected valves. Furthermore, the von Willebrand factor stained positive only on allogeneic and xenogeneic valves. Only mild differences were observed regarding the expression of integrin molecules and CD62. CONCLUSIONS: Immunological reactions play a major role in the degeneration of biological heart valve prostheses. This is underlined by observations made on aortic valves from chronically rejected cardiac grafts, which did not show any degenerative alterations. Thus, since immunosuppressive therapy after heart valve replacement is no reasonable alternative, novel and future approaches in "tissue engineering" will hopefully help avoid tissue degeneration, while preserving the advantage of biological tissue origin.     

Interactions in the aetiology,presentation and management of synchronous and metachronous adenocarcinoma of the prostate and rectum

Adenocarcinoma of the prostate and rectum are common male pelvic cancers and may present synchronously or metachronously and, due to their anatomic proximity. The treatment of rectal or prostate cancer (in particular surgery and/or radiotherapy) may alter the presentation, incidence and management should a metachronous tumour develop. This review focuses on the interaction between prostatic and rectal cancer diagnosis and management. We have restricted the scope of this large topic to general considerations, management of rectal cancer after prostate cancer treatment and vice versa, management of synchronous disease and cancer follow-up issues.