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Biomedical subjects

R Hirsch

Publications and source records attributed to R Hirsch.

At least 127 records · Page 7Linked to original sources
PubMed1989

Effects of in vivo administration of anti-CD3 monoclonal antibody on T cell function in mice. II. In vivo activation of T cells.

Anti-CD3 mAb are known to be both immunosuppressive and mitogenic to T cells in vitro. However, only immunosuppression has been observed after in vivo administration of these mAb. The present study demonstrates that T cell activation does occur after in vivo administration of anti-CD3 mAb to mice, evidenced by increased IL-2R expression on T cells, CSF secretion, and extra-medullary hematopoiesis in the spleen. These effects required multivalent cross-linking of the mAb, since F(ab')2 fragments failed to induce them. However, the F(ab')2 fragments did induce modulation of CD3/TCR from the surface of T cells, demonstrating that TCR modulation is not sufficient to induce activation. In addition, interaction of the TCR with either intact or F(ab')2 fragments of the mAb led to increased expression of CD8 in vivo, suggesting that the F(ab')2 fragments of anti-CD3 mAb might be capable of inducing a T cell to undergo some, but not all, of the changes involved in reaching a fully activated state. Further study of the activating effects of anti-CD3 mAb might increase the understanding of the mechanisms of in vivo T cell activation and might also be exploited clinically to stimulate T cell function in immunocompromised states and to enhance hematopoiesis in myelodysplastic disorders.

Animals↗
PubMed1989

T helper 2 (Th2) but not Th1 clones co-stimulate resting T cells in the presence of anti-CD3 monoclonal antibody.

We have investigated the effects of monoclonal antibody (mAb) to the CD3 epsilon protein on interactions between small, resting T cells and antigen-specific T helper clones. Highly purified, splenic T cells lacking identifiable accessory cells do not proliferate in a thymidine uptake assay to anti-CD3 mAb, Con A, rIL-2, rIL-4, or irradiated T helper clones (both Th1 and Th2). However, the responding T cells proliferate significantly to the combined stimulus of Th2 clones and anti-CD3 antibody. Only the Th2, not the Th1, subpopulation of T helper cells has the ability to induce a T cell response. The Th2 cell-dependent activation of small resting T cells does not require the external cross-linkage of the anti-CD3 mAb via Fc receptor expressing cells or the secretion of lymphokines from the Th2 helper clones, but it is inhibitable by anti-LFA 1 antibody. Thus, Th2 clones provide a co-stimulatory signal which in conjunction with anti-CD3 mAb causes resting T cell proliferation in the absence of conventional accessory cells.

Animals↗
PubMed1989

Suppression of the humoral response to anti-CD3 monoclonal antibody.

Anti-CD3 monoclonal antibodies are used clinically to treat organ allograft rejection. Their administration can result in reversal of rejection even in episodes resistant to other modes of therapy. A major limitation to their use has been the humoral response of the patients against the mAbs, resulting in loss of therapeutic efficacy. We have established an animal model for anti-CD3 treatment using the antimurine CD3 mAb, 145-2C11. Exposure of mice to this mAb, like exposure of humans to its antihuman analog OKT3, results in suppression of graft rejection but also stimulates a strong humoral response that abrogates the efficacy of further treatments. Administration of an additional dose of anti-CD3 mAb did not prolong skin graft survival--and, in some instances, resulted in a lethal anaphylactic reaction. In an attempt to suppress the humoral response against the anti-CD3 mAb, anti-CD4 mAb was administered prior to the anti-CD3 mAb treatment. Pretreatment of mice with anti-CD4 mAb (GK1.5) almost completely suppressed the humoral response to anti-CD3 mAb, and permitted readministration of the anti-CD3 mAB without loss of efficacy as assessed by prolongation of skin graft survival. The data suggest that the use of anti-CD4 mAb to suppress the humoral response against anti-CD3 mAb should be attempted clinically, as it might permit repeated courses of anti-CD3 administration, thus significantly improving the efficacy of these agents in the therapy of organ allograft rejection.

Animals↗
PubMed1989

A system for studying the selective encapsidation of hepadnavirus RNA.

All hepadnaviruses produce multiple genome-length RNA species, only one of which is encapsidated into subviral core particles prior to reverse transcription. To study the encapsidation mechanism, we developed a system in which the packaging of genetically marked target genomes of duck hepatitis B virus is mediated by factors supplied from a separate (helper) plasmid that encodes encapsidation functions. In the helper plasmid, the synthesis of the viral core and polymerase proteins was driven by a simian virus 40 promoter; the RNA produced by this construct was itself inefficiently packaged and was not active as a template for reverse transcription. Cotransfection of this construct with mutant genomes bearing frameshift lesions in either core or polymerase cistrons resulted in the successful packaging and reverse transcription of the mutant genomes. This system should allow definition of both the cis- and trans-acting elements of the encapsidation pathway.

Animals↗
PubMed1989

Direct activation of murine resting T cells by con A or anti-CD3 Ig.

The induction of antigen-specific T cell activation is highly dependent on accessory cells (AC) which present processed antigenic fragments associated with MHC molecules and provide costimulatory signals for T cells. Antigen-specific T cell activation requires cross-linking of the TCR and the reception of one or more nonantigen-specific signals which eventually lead to T cell activation and proliferation. This sequence of events can be mimicked by lectins, bacterial enterotoxins, and anti-TCR antibodies in conjunction with APC or the combination of phorbol esters and Ca ionophores. Although the combination of PMA + Ca ionophore and certain types of T-T interactions result in APC independent T cell activation, it is generally assumed that physiologic T cell activation requires APC. The seemingly direct activation of T cells by other T cells is rather surprising in view of the known APC dependence of antigen, lectin and anti-TCR mediated T cell activation. It is conceivable that T cell mediated T cell activation is due to "cryptic" APC contamination because the total absence of APC is difficult to disprove. In reality, neither total depletion nor residual contamination with APC can be proven or disproven experimentally. Thus it can be legitimately argued that both APC dependent and independent T cell activation occur, albeit under different experimental conditions. For instance, it is possible that APC independent activation of T cells by lectins and anti-TCR antibodies would require high concentrations of activators to overide their dependence on APC. It is also conceivable and, in our opinion quite likely, that once activated, T cells could propagate T cell activation through T-T interactions. In this report we test two hypotheses: (1) The triggering of resting T cells leading to autocrine cell proliferation depends entirely on cross-linking TCR molecules, and (2) The presence of activated T cells facilitates TCR mediated activation of resting T cells without the participation of conventional APC. We present evidence that highly purified, small resting T cells can be reproducibly activated with high doses of ConA, plastic bound anti-CD3 mab and its F(ab')2 fragments. This APC independent response results in blastic transformation, expression of the IL2 Receptor, the secretion of IL2 and significant proliferation of both CD4+ and CD8+ murine T cells. These observations demonstrate that vigorous cross-linking of TCRs by anti-CD3 mab and, presumably ConA, is sufficient to induce T cell activation and autocrine (IL2 driven) proliferation.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

In vivo administration of anti-CD3 prevents malignant progressor tumor growth.

Malignant progressor tumors are only weakly immunogenic and can evade host recognition and rejection. One approach to therapy involves activation of the host antitumor cellular effector mechanisms. Since monoclonal antibodies to CD3 (anti-CD3) can activate T cells in vitro, an attempt was made to determine if tumor immunity could be achieved by the administration of anti-CD3 in vivo. T lymphocytes from mice injected with anti-CD3 showed increased interleukin-2 receptor (IL-2R) expression, increased proliferation to recombinant IL-2 (rIL-2), and enhanced reactivity in both an allogeneic mixed lymphocyte reaction and a mixed lymphocyte tumor culture. Malignant tumor growth in treated mice was also examined. The anti-CD3 treatment prevented tumor outgrowth that would have killed untreated animals and also stimulated an in vivo response against a malignant progressor tumor providing lasting tumor immunity.

Animals↗
PubMed1988

Effects of in vivo administration of anti-T3 monoclonal antibody on T cell function in mice. I. Immunosuppression of transplantation responses.

Anti-T3 mAb are being increasingly used clinically in the treatment of organ graft rejection. However, there has not previously been a murine model in which the effects of these mAb on the immune system could be studied in vivo. We have established such a model using the anti-murine-T3 mAb, 145-2C11. Administration of 145-2C11 led to rapid depletion of T cells from peripheral blood and suppression of skin graft rejection. However, depletion of T cells from spleen and lymph node was both delayed and incomplete. Full recovery of T cell number was dependent on the presence of a thymus, but treatment of thymectomized animals revealed that depletion was not the mechanism by which the mAb induced immunosuppression. Rather, alterations in TCR expression may play a more important role. TCR had modulated from T cells in spleen and lymph node early after treatment, and TCR expression remained subnormal for at least 51 days posttreatment. However, subnormal TCR expression alone could not fully explain the observed T cell dysfunction, inasmuch as a period of time existed after TCR re-expression during which T cells appeared to be anergic to CTL and MLR reactivity. These findings implicate T cell dysfunction as an important element in the induction of immunosuppression after anti-T3 administration.

Animals↗
PubMed1988

Replication of duck hepatitis B virus in two differentiated human hepatoma cell lines after transfection with cloned viral DNA.

Cloned DNA of duck hepatitis B virus (DHBV) was used to transfect two differentiated human hepatoma cell lines, Huh 7 and Hep G2. Use of the transfected genome as a transcriptional template was demonstrated by the appearance of virus-specific subgenomic and genomic transcripts. Comparison of the steady-state ratio of subgenomic to genomic transcripts in Huh 7 and Hep G2 cells suggests that there are differences in the relative stability and/or rate of production of these transcripts between these cell lines. Viral genomic replication proceeded in both lines, as judged by the presence of DHBV DNA replicative intermediates in cytoplasmic core particles; the levels of these replicative intermediates is roughly equivalent in Huh 7 and Hep G2 cells. Subcutaneous injection of tissue culture medium from transfected Huh 7 cells into Pekin ducks resulted in productive DHBV infection, indicating the production and export of biologically active virus. These cell lines should provide a valuable system for studying the molecular mechanisms of the hepadnaviral life cycle.

Animals↗
PubMed1988

In vivo administration of anti-CD3 monoclonal antibody can activate immune responses thus preventing malignant tumor growth.

Anti-CD3 monoclonal antibodies (mAb) have been shown to suppress T cell-mediated immune responses both in vitro and in vivo. However, in vitro studies with these antibodies have also demonstrated that they possess potent mitogenic properties, raising the possibility that they might be capable of potentiating immune responses in vivo. In this regard, we have recently shown that an anti-CD3 mAb can activate murine T cells in vivo. Furthermore, low doses of antibody induce interleukin 2 (IL-2) receptor expression and enhanced proliferation to allogeneic major histocompatibility complex (MHC) antigen without detectable modulation or blocking of the T cell receptor and without suppression of T cell-mediated immune responses. In light of these findings, we investigated the ability of low dose anti-CD3 to enhance an anti-tumor response directed against the malignant murine UV-induced skin tumor, 1591-Pro-4L. Low dose anti-CD3 administration resulted in enhanced in vitro anti-tumor activity and prevented tumor outgrowth in approximately two-thirds of animals treated at the time of tumor inoculation. Furthermore, these animals displayed lasting tumor-specific immunity. These results suggest that anti-CD3 mAb can be utilized for the enhancement of anti-tumor responses in vivo and may have general application in the treatment of immunodeficiency.

Animals↗
PubMed1988

Fracture of the penis--review with case report.

Fracture of the penis is a rare injury. Controversy exists regarding conservative versus operative management. A case of penile fracture managed conservatively is reported with a brief review of the literature.

Adult↗
PubMed1986

A prospective study of acute hypoxic respiratory failure.

A prospective study of acute hypoxic respiratory failure was carried out by nine centers in a collaborative NIH study from 1 September 1975 to 1 March 1977. Serious hypoxic respiratory failure was defined in 713 patients by the presence of (1) endotracheal intubation and positive airway pressure for at least 24 hours, and (2) the administration of at least 50 percent oxygen. The 490 patients between 12 to 65 years of age had a mortality of 61 percent. Mortality increased with increasing organ failure: one organ system failure (lung only) 40 percent; two, 54 percent; three, 72 percent; four, 84 percent, five, 100 percent. Only 103 patients died with isolated lung failure, whereas 353 died of a combination of lung and other organ failures. Both the overall mortality (66 percent) and the mortality of those with only isolated lung failure (40 percent) were much higher than anticipated for the selection criteria.

Acute Disease↗
PubMed1985

Autoimmune hemolytic anemia as the presenting manifestation of malignant thymoma.

Severe autoimmune hemolytic anemia is described as the presenting manifestation of malignant thymoma. The hemoglobin level was 5.7 g/dl, the direct IgG antiglobulin test (direct Coombs' test) was strongly positive and the indirect Coombs' test was weakly positive. Prompt remission of the hemolytic process was achieved by thymectomy combined with corticosteroid therapy; the hemoglobin level rose to 12.2 g/dl and both the direct and indirect Coombs' tests became negative. To our knowledge, this is the first case to be described in which autoimmune hemolytic anemia was the presenting manifestation of malignant thymoma. Autoimmune hemolytic anemia may be considered as a manifestation associated with malignant thymoma.

Anemia, Hemolytic, Autoimmune↗