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Biomedical subjects

M Zeira

Publications and source records attributed to M Zeira.

At least 19 recordsLinked to original sources
PubMed2006

Post transplant persistence of host cells augments the intensity of acute graft-versus-host disease and level of donor chimerism, an explanation for graft-versus-host disease and rapid displacement of host cells seen following non-myeloablative stem cell transplantation?

Although the use of non-myeloablative stem cell transplantation (NST) reduces the severity of graft-versus-host disease (GVHD), GVHD remains a major complication following allogeneic transplantation. Since following NST in comparison with myeloablative conditioning, higher proportions of host immunohematopoietic cells may persist while donor-derived alloreactive lymphocytes are being infused, thus possibly serving as host antigen presentation for continuous stimulation of donor T cells, we speculated that GVHD may be similarly amplified by conditioning followed by intentional administration of host cells. This hypothesis was tested in a preclinical animal model. Increased incidence of GVHD, higher mortality and increased levels of chimerism were observed in recipients reconstituted with host cells, particularly with non-irradiated spleen cells. Graft-versus-leukemia effect was not impaired by post transplant cell administration. These results suggest that GVHD may be amplified by recipient cell infusion using either irradiated or viable stimulatory host cells, thus possibly explaining in part higher than anticipated incidence of GVHD and rapid displacement of host cells and conversion to 100% donor type cells following NST. Administration of irradiated host antigen-presenting cells post transplantation may thus represent a potential approach for amplification of the alloreactive capacity of donor lymphocytes following stem cell transplantation.

Animals↗
PubMed2006

Cannabidiol lowers incidence of diabetes in non-obese diabetic mice.

Cannabidinoids are components of the Cannabis sativa (marijuana) plant that have been shown capable of suppressing inflammation and various aspects of cell-mediated immunity. Cannabidiol (CBD), a non-psychoactive cannabidinoid has been previously shown by us to suppress cell-mediated autoimmune joint destruction in an animal model of rheumatoid arthritis. We now report that CBD treatment significantly reduces the incidence of diabetes in NOD mice from an incidence of 86% in non-treated control mice to an incidence of 30% in CBD-treated mice. CBD treatment also resulted in the significant reduction of plasma levels of the pro-inflammatory cytokines, IFN-gamma and TNF-alpha. Th1-associated cytokine production of in vitro activated T-cells and peritoneal macrophages was also significantly reduced in CBD-treated mice, whereas production of the Th2-associated cytokines, IL-4 and IL-10, was increased when compared to untreated control mice. Histological examination of the pancreatic islets of CBD-treated mice revealed significantly reduced insulitis. Our results indicate that CBD can inhibit and delay destructive insulitis and inflammatory Th1-associated cytokine production in NOD mice resulting in a decreased incidence of diabetes possibly through an immunomodulatory mechanism shifting the immune response from Th1 to Th2 dominance.

Animals↗
PubMed2003

Allogeneic cell-mediated immunotherapy of leukemia with immune donor lymphocytes to upregulate antitumor effects and downregulate antihost responses.

Donor lymphocyte infusion mediates most effective graft- versus-leukemia (GVL) effects following induction of host-versus-graft tolerance by transplantation of donor stem cells. This study was designed to maximize GVL effects across both major (MHC) and minor (mHgs) histocompatibility barriers in recipients inoculated with murine B-cell leukemia (BCL1), using specifically immune donor lymphocytes. GVL effects were induced with donor spleen cells from mice immunized across MHC or mHgs barriers with BCL/1 cells or normal BALB/c spleen cells. Our data suggest that spleen cells from donor mice immunized against murine B-cell leukemia of BALB/c origin, or to a lesser extent against normal host alloantigens, induce better therapeutic GVL effects with less great-versus-host disease (GVHD) across both mHgs and MHC. The cytokine profile of effector cells inducing predominantly GVL effects with reduced GVHD across MHC and mHg barriers consisted preferentially of upregulated IFN-gamma, IL-2, IL-10 and IL-12 in donors, implying a Th-1 to Th-2 cytokine shift. We hypothesize that immunotherapy with immune donor lymphocytes sensitized in vivo or in vitro with allogeneic tumor cells or normal host cells together with allogeneic BMT may provide an effective approach for amplifying GVL effects, while reducing procedure-related morbidity and mortality due to uncontrolled GVHD.

Animals↗
PubMed2000

Induction of oral tolerance in splenocyte recipients toward pretransplant antigens ameliorates chronic graft versus host disease in a murine model.

Chronic graft versus host disease (cGVHD) is a major complication that can develop after bone marrow transplantation. It involves an immune-mediated attack by transplanted donor lymphocytes, and often results in inflammatory damage of host target organs. Immune hyporesponsiveness induced by oral antigen administration has been recently shown to prevent the development of cGVHD in a murine model. The aim of this study was to evaluate whether tolerance induction in bone marrow transplant (BMT) recipients after transplantation, toward their pretransplant antigens, can alleviate preexisting cGVHD in a mouse model. cGVHD was generated by infusing 2.5 x 10(7) splenocytes from B10.D2 donor mice, to sublethally irradiated (6 Gy) BALB/c recipient mice, which differ by minor histocompatibility antigens. Transplantation resulted in cGVHD, with characteristic scleroderma-like cutaneous fibrosis, increased skin collagen content, decreased body weight, and hepatic and small bowel inflammation. Oral tolerance was induced by feeding recipient BALB/c mice with proteins extracted from BALB/c splenocytes for 11 days after B10.D2 splenocyte transplantation. Tolerance induction was evidenced by a significant reduction in mixed lymphocyte response of effector splenocytes from tolerant BALB/c mice transplanted with B10.D2 splenocytes against BALB/c target splenocytes. Oral tolerance decreased skin collagen deposits. Reduction of collagen alpha1(I) gene expression and skin collagen were shown by in situ hybridization and histochemistry, respectively. Liver and bowel biopsy specimens revealed less inflammation. Serum IL-10 levels were higher in tolerant mice than in controls, whereas IFNgamma was significantly reduced. Oral tolerance of BMT recipients toward their pretransplant antigens after splenocyte transplantation down-regulated the immune attack by transplanted cells, thus ameliorating cGVHD.

Administration, Oral↗
PubMed2000

Oral tolerization ameliorates liver disorders associated with chronic graft versus host disease in mice.

In chronic graft versus host disease (cGVHD), an immune attack by transplanted donor lymphocytes results in damage of host target organs. A disbalance between proinflammatory (Th1) and anti-inflammatory cytokines (Th2) plays an important role in the pathogenesis. Immune hyporesponsiveness induced by oral antigen administration has been shown to suppress autoimmunity. We evaluated the efficacy of oral tolerization in preventing cGVHD in a mouse model. cGVHD was generated by infusing 2.5 x 10(7) splenocytes from B10.D2 donor mice, to sublethally irradiated (6 Gy) BALB/c recipient mice, which differ in minor histocompatibility antigens. The transplantation resulted in cGVHD, with characteristic hepatic and small bowel inflammation, and increased skin collagen content and fibrosis. Oral tolerance was induced by feeding donor B10.D2 mice with proteins extracted from BALB/c splenocytes at 50 microg/d per mouse for 11 days before transplantation. Tolerization was evidenced by reduction in mixed lymphocyte response of effector splenocytes from tolerized B10.D2 mice against BALB/c target splenocytes. Liver and small bowel biopsy specimens revealed much less inflammation. Oral tolerization prevented weight and subcutaneous fat loss, reduced thickening, and skin collagen deposits. Reduction of collagen alpha1 (I) gene expression was shown by in situ hybridization. Serum interleukin 10 (IL-10) levels measured significantly higher in tolerized mice than in controls, whereas interferon gamma (IFN-gamma), IL-2, and tumor necrosis factor alpha (TNF-alpha) were reduced significantly. Oral tolerization of splenocyte donors towards recipient-strain splenocytes ameliorated cGVHD of the liver, small intestine, and skin. A cytokine shift from a proinflammatory to an anti-inflammatory pattern may play a role in down-regulation of the immune-mediated target organ damage.

Animals↗
PubMed1993

[Pregnancy and delivery in women with coarctation of the aorta].

We report 2 cases of aortic coarctation in women aged 18.5 and 24 years, respectively. In 1 the malformation was found during gestation, while the other became pregnant after the diagnosis was made. Both had uneventful pregnancies and delivered healthy babies. Coarctation of the aorta is found in approximately 7% of those with congenital heart disease. The clinical diagnosis is made from the absence of femoral artery pulsations and low arterial pressure in arteries originating distal to the coarctation and hypertension in those proximal to it. Since it occurs mainly in males and is usually corrected during infancy, its incidence in pregnancy is low. Maternal morbidity may be high, since pregnancy increases the risk of aortic rupture or dissection, as well as of cerebral hemorrhage from rupture of an aneurysm of the circle of Willis. Surgical repair before conception reduces the risk of aortic complications during pregnancy, and also decreases the incidence of fetal complications, such as IUGR or congenital heart disease. The outcome of pregnancy is also influenced by coexistence of other malformations, such as bicuspid aortic valve which leads to infective endocarditis. In uncomplicated coarctation, pregnancy and delivery are usually uneventful. Cesarean section is done mainly for obstetric indications.

Adult↗
PubMed1992

Virus-cell membrane fusion does not predict efficient infection of alveolar macrophages by human immunodeficiency virus type 1 (HIV-1).

Alveolar macrophages (AM) are the principal target cells for HIV-1 in lung tissue. To investigate the mechanisms of HIV-1 infection and efficient replication in these cells we isolated AM from 14 HIV-1 negative donors and exposed them to two virus isolates, either N1T, which replicates well in T lymphocytic and monocytic cell lines, or ADA, a monocytotropic virus. Membrane fluorescence dequenching assays demonstrated that HIV-1/N1T fuses efficiently with AM plasma membranes at neutral pH and that this interaction requires cellular CD4. Despite efficient fusion, AM from eight of 14 donors were not susceptible to productive infection with N1T. In contrast, ADA replicated in all AM populations tested. Soluble CD4 blocked infection of AM by either N1T or ADA, indicating that, like membrane fusion, entry of infectious virus requires an interaction with cellular CD4. Analysis of HIV-1 DNA accumulation in infected cells by enzymatic amplification revealed that productive infection by ADA correlated with a high HIV-1 DNA copy number and abortive infection by N1T was characterized by little or no stable cDNA. These studies suggest that the differences between the two HIV-1 strains studied in their ability to replicate in AM reside in phases of the virus life cycle that follow virus-cell fusion.

CD4 Antigens↗
PubMed1991

Full-length CD4 electroinserted in the erythrocyte membrane as a long-lived inhibitor of infection by human immunodeficiency virus.

Recombinant full-length CD4 expressed in Spodoptera frugiperda 9 cells with the baculovirus system was electroinserted in erythrocyte (RBC) membranes. Of the inserted CD4, 70% was "correctly" oriented as shown by fluorescence quenching experiments with fluorescein-labeled CD4. The inserted CD4 displayed the same epitopes as the naturally occurring CD4 in human T4 cells. Double-labeling experiments (125I-CD4 and 51Cr-RBC) showed that the half-life of CD4 electroinserted in RBC membrane in rabbits was approximately 7 days. Using the fluorescence dequenching technique with octadecylrhodamine B-labeled human immunodeficiency virus (HIV)-1, we showed fusion of the HIV envelope with the plasma membrane of RBC-CD4, whereas no such fusion could be detected with RBC. The dequenching efficiency of RBC-CD4 is the same as that of CEM cells. Exposure to anti-CD4 monoclonal antibody OKT4A, which binds to the CD4 region that attaches to envelope glycoprotein gp120, caused a significant decrease in the dequenching of fluorescence. In vitro infectivity studies showed that preincubation of HIV-1 with RBC-CD4 reduced by 80-90% the appearance of HIV antigens in target cells, the amount of viral reverse transcriptase, and the amount of p24 core antigen produced by the target cells. RBC-CD4, but not RBCs, aggregated with chronically HIV-1-infected T cells and caused formation of giant cells. These data show that the RBC-CD4 reagent is relatively long lived in circulation and efficient in attaching to HIV-1 and HIV-infected cells, and thus it may have value as a therapeutic agent against AIDS.

Animals↗
PubMed1991

Thymocyte maturation following interaction with thymus-derived macrophages.

Murine C57BL/6 thymocytes were cultivated together with syngeneic thymus-derived macrophages (TDM phi) for up to 96 hr to determine whether TDM phi participate in thymocyte maturation. The expression level of H-2b and Thy-1.2 antigens served as thymocyte differentiation surface markers as analyzed by flow cytometry. Indirect immunofluorescent staining profiles of the thymocytes demonstrate a dramatic increase in H-2b expression and a profound decrease in Thy-1.2 expression during cultivation with TDM phi. A similar phenomenon was observed when enriched populations of immature thymocytes were cocultivated with TDM phi. These changes were not observed when thymocytes were cultivated alone or with trypsin-treated TDM phi; neither were they observed when cortisone-resistant thymocytes manifesting mature characteristics were cultivated together with TDM phi. These findings suggest that interaction of thymocytes with TDM phi, involving binding and engulfment, results in the appearance of mature thymocyte subsets.

Animals↗
PubMed1990

Human immunodeficiency virus infection of human bone marrow stromal fibroblasts.

The human immunodeficiency virus (HIV) preferentially infects CD4 positive T cells and monocytes. Other human cell types have been reported to be infectable with HIV, including cells of mesenchymal origin. In this report, we show that both primary human bone marrow stromal fibroblasts and an immortalized human stromal fibroblast line are susceptible to HIV infection. These cells are capable of passing HIV to cells of lymphoid or myeloid lineage, and may thereby act as a reservoir of virus. This in vitro system may be a useful model for assessing the pathophysiology of hematopoietic dysfunction in AIDS patients.

Actins↗
PubMed1990

Inhibition of serum-enhanced HIV-1 infection of U937 monocytoid cells by recombinant soluble CD4 and anti-CD4 monoclonal antibody.

Mononuclear phagocytes can be infected with the human immunodeficiency virus type 1 (HIV-1). Although these cells express CD4 antigen, which is the recognized cellular receptor for HIV, additional cell surface proteins such as the Fc receptor, might serve as receptors for infection. In order to study this possibility we used the U937 monocytic cell line as a target for HIV infection. Flow cytometry of U937 showed that 97% of cells expressed CD4, 33% expressed the high affinity 72 kD Fc receptor (FcRI), and 74% expressed the low-affinity 40 kD Fc receptor (FcRII). Virus neutralization tests were performed by preincubating heat-inactivated human anti-HIV sera with HIV-1, IIIB strain, and then challenging U937. After 13 days in culture, productive HIV-1 infection was monitored by reverse transcriptase activity. High concentrations of certain sera (10(-1)-10(-3) dilutions) neutralized HIV-1, but at subneutralizing concentrations (10(-4)-10(-6) dilutions), five of these sera enhanced viral infection approximately two- to threefold. This enhancement of HIV-1 infection was totally blocked by 1 microgram/ml recombinant soluble CD4 (rCD4) or by 0.5 microgram/ml anti-CD4 Leu3a monoclonal antibody. These results suggest that serum enhancement of HIV-1 infection, thought to be due to binding to the monocyte Fc receptor, requires HIV-1 binding to CD4, since rCD4 or Leu3a blocked this phenomenon.

AIDS-Related Complex↗
PubMed1990

Effect of strain and age on in vitro proliferation of murine thymus-derived macrophages.

In our laboratory we developed a technique which enabled us to carry out long term cultures of pure murine thymus-derived macrophage (TDM phi) populations having morphology, phagocytic capacity and surface markers characteristic of mononuclear phagocytic cells. We cultured thymic cells derived from various mouse strains on extracellular matrix coated tissue culture dishes, in the presence of conditioned medium. These cells developed into discrete TDM phi colonies and demonstrated a different proliferation rate. The TDM phi bearing haplotype H-2k (C3H/Crgl, CBA/LAC) proliferated more rapidly than TDM phi derived from mouse strains bearing the haplotypes of H-2b (C57BL/6), H-2d (BALB/c) and H-2k/d (A/J). To evaluate more precisely the number of precursor cells which generated TDM phi colonies and to study their growth kinetics, thymic cells were cultured in soft agar. A relatively large number of TDM phi precursor cells was derived from thymuses of H-2k haplotype origin. These precursor cells manifested a high rate of proliferation as compared with precursor cells of other murine haplotypes studied (H-2b, H-2d). These observations suggest that macrophage precursor cells are also located in the thymus and their numbers are controlled by genetic factors. We also observed a correlation between the number of precursor cells and the age of the mice. The percentage of TDM phi in new born and young mice was approximately four times higher than that found in older mice. It, therefore, seems that the degree of thymic involution affects the number of thymic macrophage precursor cells, which might indirectly affect thymocyte maturation and/or differentiation.

Age Factors↗
PubMed1988

Interaction between thymocytes and thymus-derived macrophages. I. Surface components participating in mutual recognition.

Incubation of C57BL/6 thymus-derived macrophages (TDM phi) with syngeneic thymocytes resulted in binding of thymocytes to macrophages and rosette formation. Up to 60% of the TDM phi formed rosettes with thymocytes after 6 hr of interaction at 4 degrees C. Rosette formation of the immature PNA+ thymocyte fraction was up to fivefold higher than that of PNA- and cortisone-resistant thymocytes. Pretreatment of PNA- thymocytes with neuraminidase enhanced thymocyte binding to macrophages up to sevenfold, whereas a marked reduction of rosette formation was seen following (1) incubation of thymocytes with tunicamycin; (2) incubation of macrophages with 20 mM D-galactose, GLCNaC, or GalNaC; (3) treatment of macrophages or thymocytes with trypsin; (4) treatment of macrophages with anti-1-Ab mAb and its F(ab')2 fragment; (5) treatment of thymocytes with anti-Lyt-2.2 mAb; and (6) addition of EDTA and EGTA to the interacted two cell populations.

Animals↗
PubMed1988

Interaction between thymocytes and thymus-derived macrophages. II. Engulfment of thymocytes by macrophages.

A high percentage (80-90%) of immature thymocytes were engulfed by syngeneic thymus-derived macrophages (TDM phi) following cocultivation for 3 days. Elimination occurred via internalization of thymocytes by the macrophages. We unequivocally demonstrated the presence of many live thymocytes inside the TDM phi by means of specific staining. Mature PNA- thymocytes were phagocytized to a lower degree than immature thymocytes, and T splenocytes were not eliminated at all. Bone marrow-derived macrophages internalized immature thymocytes to a degree similar to TDM phi. Since thymocyte survival was not at all affected by M phi culture supernatants alone, we conclude that cell to cell contact is necessary for thymocyte elimination. To identify the surface molecules which participate in internalization of thymocytes by the macrophages, both cell types were pretreated with a variety of agents. Treatment of thymocytes with tunicamycin (N-glycosylation inhibitor) and anti-Lyt-2 mAb decreased their elimination by M phi. Similarly, treatment of M phi with neuraminidase, trypsin, and anti-Ia mAb markedly suppressed their capacity to engulf thymocytes. On the other hand, thymocyte elimination was unaffected by (1) cell cultivation in syngeneic serum rather than heterologous serum; (2) use of allogeneic rather than syngeneic thymocytes; and (3) use of X-irradiated M phi and LPS-activated M phi rather than nontreated M phi.

Animals↗
PubMed1985

Thymus-derived macrophages in long-term culture: release of IL-1, stimulation of MLR and expression of tumoricidal activity.

The present report examines the behaviour of a slowly proliferating pure population of thymus-derived macrophages in long-term culture, regarding their ability to secrete interleukin-1 (IL-1) and prostaglandin E2 (PGE2), to stimulate a mixed leucocyte reaction (MLR) and to lyse tumour cells in vitro. Following stimulation with LPS, high levels of IL-1 were released to the medium. IL-1 release was significantly augmented by the addition of indomethacin during stimulation. Thymus-derived macrophages constitutively secreted significant levels of PGE2. These cells served as excellent stimulators in a one-way MLR, substantiating the claim that pure populations of macrophages effectively stimulate an allogeneic response in vitro. Thymus-derived macrophages showed tumoricidal activity following activation with either high concentrations of LPS or suboptimal concentrations of LPS and T-cell lymphokine. These findings portray a close interrelationship and reciprocal regulation between thymus-derived macrophages and T lymphocytes.

Animals↗