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L Horwitz

Publications and source records attributed to L Horwitz.

At least 19 recordsLinked to original sources
PubMed1999

C6 produced by macrophages contributes to cardiac allograft rejection.

The terminal components of complement C5b-C9 can cause significant injury to cardiac allografts. Using C6-deficient rats, we have found that the rejection of major histocompatibility (MHC) class I-incompatible PVG.R8 (RT1.A(a)B(u)) cardiac allografts by PVG.1U (RT1.A(u)B(u)) recipients is particularly dependent on C6. This model was selected to determine whether tissue injury results from C6 produced by macrophages, which are a conspicuous component of infiltrates in rejecting transplants. We demonstrated that high levels of C6 mRNA are expressed in isolated populations of macrophages. The relevance of macrophage-produced C6 to cardiac allograft injury was investigated by transplanting hearts from PVG. R8 (C6-) donors to PVG.1U (C6-) rats which had been reconstituted with bone marrow from PVG.1U (C6+) rats as the sole source of C6. Hearts grafted to hosts after C6 reconstitution by bone marrow transplantation underwent rejection characterized by deposition of IgG and complement on the vascular endothelium together with extensive intravascular aggregates of P-selectin-positive platelets. At the time of acute rejection, the cardiac allografts contained extensive perivascular and interstitial macrophage infiltrates. RT-PCR and in situ hybridization demonstrated high levels of C6 mRNA in the macrophage-laden transplants. C6 protein levels were also increased in the circulation during rejection. To determine the relative contribution to cardiac allograft rejection of the low levels of circulating C6 produced systemically by macrophages, C6 containing serum was passively transferred to PVG.1U (C6-) recipients of PVG.R8 (C6-) hearts. This reconstituted the C6 levels to about 3 to 6% of normal values, but failed to induce allograft rejection. In control PVG.1U (C6-) recipients that were reconstituted with bone marrow from PVG.1U (C6-) donors, C6 levels remained undetectable and PVG.R8 cardiac allografts were not rejected. These results indicate that C6 produced by macrophages can cause significant tissue damage.

Animals↗
PubMed1999

The utility of quantitative body surface isoarea mapping for predicting ventricular tachyarrhythmias.

Noninvasive techniques, such as the signal averaged ECG, have been used to assess risk of ventricular tachyarrhythmias (VT). However, these methods produce false positive and negative results. The purpose of this study was to develop body surface map algorithms which would enhance prediction of susceptibility to VT. Fifty-three patients referred for programmed electrical stimulation were enrolled in this study. All patients underwent signal averaged ECG, body surface map, programmed electrical stimulation. Group I patients had no sustained inducible VT and group II patients had either inducible sustained VT at electrophysiology study or previously documented spontaneous, sustained VT. For body surface map analysis, the difference between extrema on isoarea maps was calculated and defined as the gradient range. An abnormal body surface map was defined as a QRST gradient range < or = 109 mv.ms. The mean QRST gradient range in group II was significantly < that in group I (P < 0.05). By logistic regression analysis, the presence of coronary artery disease, a QRST gradient range < or = 109 mv.ms, an EF < 40% and a signal averaged ECG QRS duration > 114 ms predicted VT. The sensitivity, specificity, positive and negative predictive values for predicting VT susceptibility of an algorithm which combines the signal averaged ECG QRS duration and the QRST gradients were 0.93, 0.76, 0.79, and 0.91, respectively, while those for the signal averaged ECG alone were 0.52, 0.69, 0.63, and 0.59 for VT susceptibility. A combined body surface map-signal averaged ECG algorithm was more sensitive in detecting susceptibility to VT than the signal averaged ECG alone.

Adolescent↗
PubMed1999

A noble profession.

Organized psychoanalysis has now achieved an era of openness to new ideas and change, and the result has been an exciting ferment in both theory and technique. Most recently, the field has focused on "intersubjectivity," the study of how the therapist's personality acts and reacts with that of the patient. Despite the subjectivities inherent in the process of treatment, there is good justification for viewing the field as an empirical discipline, indeed a science, because the multiple inputs by practitioners contributing to the literature, debating on panels, and critically assessing new contributions result in a gradual approach to truth and validity. This hermeneutic approach is not sufficient in itself and in no way contradicts the need for other, more controlled, research approaches.

Humans↗
PubMed1998

Promiscuous recognition of major histocompatibility complex class II determinants in cyclosporine-induced syngeneic graft-versus-host disease: specificity of cytolytic effector T cells.

BACKGROUND: Administration of the immunosuppressive drug cyclosporine after syngeneic/autologous bone marrow transplantation paradoxically elicits a systemic autoimmune syndrome resembling graft-versus-host disease (GVHD). This syndrome, termed autologous or syngeneic GVHD, is associated with the development of a highly restricted repertoire of cytolytic T lymphocytes that promiscuously recognizes major histocompatibility complex class II determinants, including self. METHODS: Vbeta8.5+CD8+ effector lymphocytes and T-cell clones were isolated from Lewis rats with cylosporine-induced syngeneic GVHD. The specificity of the effector T cells and T-cell clones was examined in vitro. The pathogenicity of the T-cell clones was confirmed in vivo using a local graft-versus-host reaction assay. RESULTS: Clonal analysis reveals that the pathogenic effector T cells recognize a peptide from the invariant chain termed CLIP in association with major histocompatibility complex class II determinants. Moreover, there appears to be an additional interaction between the N-terminal flanking region of CLIP and the Vbeta segment of the T cell receptor. CONCLUSION: The results suggest that recognition of this highly conserved peptide along with the additional interaction between the flanking region and the T cell receptor may account for the promiscuous activity of the autologous/syngeneic GVHD autoreactive T cells.

Amino Acid Sequence↗
PubMed1997

Prevention of coronary vascular abnormalities early in reperfusion with TGF-beta may not prevent late coronary vascular injury.

Endothelial injury, manifest by increased protein leak and decreased endothelium-dependent relaxation, occurs during reperfusion after ischemia. Transforming growth factor-beta (TGF-beta) has been shown to improve endothelium-dependent relaxation and reduce infarct size after short periods (from 20 min to 4.5 h) of reperfusion even when administered 24 h before the ischemic period. However, whether this represents a transient delay in the process leading to endothelial injury or prevention of injury has not been clear. To examine this issue, we measured protein leak, an index of coronary microvascular permeability, and endothelium-dependent relaxation, a measure of coronary endothelial function, after brief (1-h) and lengthy (48-h) reperfusion periods in dogs treated 30 min before ischemia with TGF-beta (30 microg/kg, i.v.) and control dogs. The left anterior descending coronary artery (LAD) was ligated for 1 h followed by 1 h of reperfusion (n = 10) or 48 h of reperfusion (n = 12). Protein leak was assessed by a dual-isotope technique by using radiolabeled transferrin and erythrocytes, and endothelium-dependent relaxation was assessed in epicardial coronary rings by using adenosine diphosphate (ADP), an endothelium-dependent vasodilator, and sodium nitroprusside (SNP), an endothelium-independent dilator. In control animals, there was a marked increase in the protein leak index (PLI) in the infarct zone (8.3 +/- 1.4 in 1-h dogs, and 8.7 +/- 0.9 in 48-h dogs) compared with the nonischemic myocardium (3.1 +/- 0.8 at 1 h, and 3.8 +/- 0.9 at 48 h). In TGF-beta treated dogs, there was a marked improvement in PLI in the infarct zone in 1-h dogs (PLI, 4.1 +/- 1.1; p < 0.05; or a 50% reduction compared with untreated dogs). However, the 48-h dogs treated with TGF-beta failed to demonstrate an improvement in PLI (PLI, 8.5 +/- 0.9; p = NS). Endothelium-dependent relaxation was impaired in the LAD in control dogs, and treatment with TGF-beta failed to improve relaxation after 1 or 48 h of reperfusion. Microvascular permeability was increased and endothelium-dependent relaxation was decreased after ischemia at both 1 and 48 h of reperfusion. Pretreatment with TGF-beta reduced the increase in permeability at 1 h of reperfusion but not at 48 h.

Animals↗
PubMed1996

Development of an interactive computer-guided method for radiofrequency catheter ablation of ventricular tachycardia.

The purpose of this study was to develop a simple computer-guided approach to localizing ventricular tachycardias during ventricular mapping. Six patients with sustained monomorphic ventricular tachycardia were connected to a 32-lead computer body surface mapping system. Isoarea maps of induced ventricular tachycardia were recorded. Then a pacing probe was placed in either the right or left ventricle, and maps were generated from a variety of sites. Differences between ventricular tachycardia and pace map maxima X, Y coordinates were utilized to guide catheter manipulation and localization. In 6 of 6 patients (100%) this method appeared to provide a systematic approach to ventricular tachycardia localization. Computer-generated correlations as well as the X, Y coordinates of the QRS isoarea maxima were used to determine proximity to the ventricular tachycardia foci and direct catheter manipulation. In the next three patients this method was applied prospectively to help guide catheter manipulation during ventricular tachycardia (two right ventricular outflow tract tachycardias, and one left ventricular tachycardia). After a mean of 4.0 +/- 1.7 radiofrequency applications, ventricular tachycardia was no longer inducible, and at 7 +/- 0 months follow-up there have been no arrhythmia recurrences. We conclude that online computerized body surface mapping can assist in localizing ventricular tachycardia. Differences in maxima during pace maps and in-situ ventricular tachycardias can help with catheter manipulation as well as with more precise identification of focal tachycardias. This technique appears to hold the promise of a simple computer-guided method that may facilitate radiofrequency catheter ablation.

Adult↗
PubMed1995

The role of cyclosporine-induced autoreactive T lymphocytes in solid organ allograft survival and chronic rejection.

Cyclosporine (CsA) has profound but paradoxical effects on the immune system. CsA can facilitate the induction of transplantation tolerance in some animal systems but it inhibits the clonal deletion of MHC class II autoreactive T cells. The present studies evaluated whether the autoreactive T cells participate in the induction of facilitated graft acceptance after CsA treatment by recognizing and eliminating activated allograft responsive T cells that express MHC class II determinants. Transfer of autoreactive T cells into naive Lewis rats pretreated with cyclophosphamide significantly prolonged the survival of heterotopic cardiac allografts from MHC-disparate BN strain donors. Following transfer of the autoreactive T cells, there was a marked reduction in the frequency of alloreactive T lymphocytes responsive to donor alloantigens. The role of MHC class II autoreactive CD8+ V beta 8.5+ T cells in facilitated graft acceptance was also supported by the findings that (1) treatment with anti-MHC class II antibody abrogated prolonged allograft survival after CsA therapy and (2) V beta 8.5+ lymphocytes infiltrate the allograft during CsA therapy but are absent in the graft in non-CsA-treated control animals. Although these data are consistent with the hypothesis that autoreactive T cells prolong cardiac allograft survival after CsA treatment, the autoaggressive cells failed to inhibit the development of chronic rejection of both heart and skin allografts. These data suggest either that the autoreactive T cells do not inhibit immune mechanisms responsible for chronic graft rejection or that the autoaggressive lymphocytes may participate in and exacerbate chronic rejection of allografts. Taken together, the induction of MHC class II autoreactive T cells may provide a common fundamental mechanism explaining the paradoxical effects of CsA.

Animals↗
PubMed1994

Characterization of peripheral autoregulatory mechanisms that prevent development of cyclosporin-induced syngeneic graft-versus-host disease.

Administration of cyclosporin after syngeneic bone marrow transplantation paradoxically elicits a T lymphocyte-dependent autoaggression syndrome termed syngeneic graft-vs-host disease (SGVHD). The induction of SGVHD requires two essential components, the emergence of autoreactive lymphocytes from the thymus and the elimination of a T cell-dependent peripheral autoregulatory mechanism. These studies used the SGVHD model to further characterize this regulatory system that modifies the autoimmune potential of autoreactive effector cells. Our studies reveal that although cyclosporin did not interfere with the effector function of the autoregulatory T cells, it prevented the reconstitution of the regulatory system after syngeneic bone marrow transplantation. Furthermore, the autoregulation of SGVHD is a dynamic process specifically recognizing and responding to the autoreactive SGVHD effector cells. Challenge or priming of normal Lewis rats by intravenous infusion of irradiated SGVHD effector cells activates and amplifies this autoregulatory system resulting in: 1) a threefold enhancement of autoregulatory T cell function, 2) the appearance of a dominant autoregulatory T cell population belonging to the CD4+ T helper lymphocyte subset, and 3) the capacity of irradiated primed autoregulatory T cells to inactivate SGVHD effector lymphocytes in vitro. Additional studies reveal that effective autoregulation required a specific interaction of the TCR-alpha/beta on the autoregulatory cells with the MHC class II determinants on the autoreactive lymphocytes.

Animals↗
PubMed1994

Depth of transference in groups.

An ongoing controversy in the field of group psychotherapy is whether transference regression is greater in groups than in individual treatment. There appears to be a general consensus that group behavior may be understood as operating on at least three levels--the conscious--rational, the oedipally determined transference, and the preoedipal maternal transference level. The more rational levels are associated with transference dilution, whereas the more primitive levels accompany transference intensification. Dilution occurs as a result of reality demands and inputs of the group situation and because of multiple targets of displacement. Transference intensification is a product of mutual stimulation, contagion effect, frustrating inputs, and support of the group theme. Certain patients benefit most from the dilution features of a group, and others profit most from intensification. The therapist's technique and the patient's pathology are the main determinants of which aspect gets emphasized and utilized.

Humans↗
PubMed1994

The transition process in converting to psychoanalysis.

Numerous psychological factors are involved in converting from psychotherapy to psychoanalysis with the same analyst. The process of making the recommendation and working through reactions to it, both before and after the analysis begins, requires heightened attention to the ensuing transference and countertransference reactions. After reviewing the literature on this area, the author highlights the main factors in this process and presents an illustrative case example.

Adult↗
PubMed1992

Interferon-gamma potentiates the antitumor effect of cyclosporine-induced autoimmunity.

Graft-versus-host-disease (GVHD), which results after allogeneic bone marrow transplantation (BMT), is associated with reduced leukemic relapse. This may be mediated by an immunologic attack with subsequent destruction of residual tumor cells. On the other hand, GVHD does not normally occur after autologous BMT (ABMT), which has an inherently high relapse rate. However, an autoimmune syndrome (AIS) similar to GVHD can be induced after autologous/syngeneic BMT by administration of cyclosporine-A (CsA), resulting in the production of major histocompatibility complex (MHC) class II or Ia autoreactive cytolytic effector cells. Since many hematopoietic malignancies express variable levels of class II molecules, we hypothesized that the adjuvant use of interferon-gamma (IFN-gamma) with CsA-induced autoimmunity after autologous/syngeneic BMT may upregulate class II antigens on residual tumor cells and make them more susceptible to attack by the Ia-reactive cells of CsA-induced AIS. The present studies demonstrated that the CsA-induced autoimmune syndrome mediated an anti-tumor effect, although this effect was dependent on challenge with a minimal number of tumor cells. Further studies clearly demonstrated that the antitumor effect could be markedly enhanced by administration of IFN-gamma which increased the susceptibility of the tumor to recognition and lysis by the CsA induced autoimmune effector cells. The induction of MHC class II-restricted AIS similar to GVHD by administration of CsA together with the ability to manipulate the surface phenotype of residual tumor cells may lead to decreased relapse rates in the ABMT setting.

Animals↗
PubMed1991

Effect of cyclosporine on T lymphocyte development. Relationship to syngeneic graft-versus-host disease.

This report investigates the effects of cyclosporine on the reconstitution of T lymphocytes after syngeneic bone marrow transplantation and its role in the development of a novel T cell-mediated autoimmune disease, syngeneic graft versus host disease. We analyzed the effect of CsA treatment on T lymphocyte differentiation during reconstitution after bone marrow transplantation and correlated the maturation of CD4+ and CD8+ T cell subsets with the onset of syngeneic GVHD. Administration of CsA following syngeneic bone marrow transplantation leads to a developmental arrest of mature CD4+ and CD8+ T lymphocytes in the thymus and a marked reduction in cells expressing the alpha beta T cell receptor. The reduction of CD4+ and CD8+ T cell subsets is also reflected in the peripheral lymphoid compartment with an altered CD4/CD8 ratio. Functional assessment of the cells revealed that CD8+ cells respond normally to mitogenic signalling whereas CD4+ cells exhibit marginal proliferative responses. Both subsets of T lymphocytes respond to syngeneic B lymphoblasts, comparable to the response of T lymphocytes from non-CsA-treated syngeneic BMT recipients, suggesting that autoreactive cells are produced despite CsA treatment. Following discontinuation of CsA, T cell differentiation in the thymus is rapidly restored to normal. However, concurrent with the onset of syngeneic GVHD, a compensatory insurgence of CD4+ T helper cells is observed.

Animals↗
PubMed1989

Host resistance to cyclosporine induced syngeneic graft-versus-host disease. Requirement for two distinct lymphocyte subsets.

Cyclosporine is crucial for the prevention of organ allograft rejection and allogeneic graft-vs-host disease (GVHD). Despite its potent immunosuppressive activity, cyclosporine elicits a T cell-mediated autoimmune syndrome after autologous or syngeneic bone marrow transplantation, which has been termed syngeneic GVHD (SGVHD). Recent studies have shown that for disease manifestation, a cytoxan and radiation-sensitive T cell dependent host resistance mechanism must be eliminated, allowing the clonal expansion of autoreactive cells. This report characterizes the autoregulatory lymphocyte population, present in normal animals, capable of inhibiting the adoptive transfer of SGVHD. First, twice the number of unfractionated splenocytes from normal animals to those from autoimmune donors ensured complete inhibition of the adoptive transfer of immune reactivity. Second, the phenotype of this host resistance mechanism in normal splenocytes involves dual regulatory T cell subsets. A helper/inducer subset (W3/25+) must be cotransferred with a cytotoxic/suppressor subset (OX8+) in a ratio that approximates the normal ratio in normal unfractionated splenocytes in order to affect inhibition of the transfer of SGVHD. Moreover the specific inducer regulatory activity resides in the OX22-, W3/25+ subset of Th cells.

Animals↗
PubMed1988

The effect of therapist interventions on the therapeutic alliance with borderline patients.

The authors draw attention to the problems of establishing and maintaining a therapeutic alliance in the psychotherapy of the borderline patient. They elaborate an extensive methodology designed to study the manner in which shifts in collaboration occur in response to therapist interventions. This report demonstrates how one particular borderline patient increased his ability to collaborate with the therapist in response to a transference focus in the psychotherapy. Methodological problems are noted as are directions for future research. Only a series of patients studied with this or with similar methodology will allow for a sophisticated and empirical rationale for choosing a particular form of psychotherapy for a particular kind of borderline patient.

Adult↗