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Biomedical subjects

A D Hess

Publications and source records attributed to A D Hess.

At least 37 records · Page 2Linked to original sources
PubMed1995

Extrahepatic synthesis of C6 in the rat is sufficient for complement-mediated hyperacute rejection of a guinea pig cardiac xenograft.

The liver is the major source of complement (C) components, but extrahepatic sources of C, such as macrophages and endothelial cells, have been hypothesized to contribute to inflammation. Our experiments demonstrate that extrahepatically produced C6 can contribute to hyperacute rejection. PVG (RT1c) rats with normal C activity (PVG (C+)) reject guinea pig cardiac xenografts in 0.5 +/- 0.2 hr, but fully C6-deficient PVG (RT1c) rats (PVG (C-)) reject guinea pig cardiac xenografts in 45 +/- 9 hr. PVG (C+) rats, which received liver transplants from PVG (C-) rats and retained all extrahepatic sources of C6, rejected guinea pig cardiac xenografts in 0.6 +/- 0.03 hr (n = 3). PVG (C-) rats, which received bone marrow transplants from PVG (C+) rats, had C6 levels restored to 10% of that of the donor and rejected guinea pig cardiac xenografts in 9 +/- 3.2 hr (n = 5). Thus, extrahepatic sources of C6 can contribute to xenograft rejection.

Animals↗
PubMed1995

Characterization of the autoreactive T cell repertoire in cyclosporin-induced syngeneic graft-versus-host disease. A highly conserved repertoire mediates autoaggression.

Syngeneic graft-vs-host disease (SGVHD) is a MHC class II-restricted T cell-mediated autoimmune syndrome that occurs following syngeneic bone marrow transplantation and the administration of cyclosporin (CsA). The present studies evaluated the V beta repertoire of T lymphocytes that mediate SGVHD. To facilitate analysis, SGVHD effector cells were adoptively transferred into thymectomized syngeneic recipients reconstituted with T cell-depleted bone marrow to provide an environment that allows for the selective clonal expansion of autoreactive T cells. Analysis of target tissues and PBL by reverse transcriptase PCR using oligonucleotide V beta-specific primers revealed a predominance of V beta 8.5+ T cells and a minor population expressing V beta 10. The majority of infiltrating lymphocytes in target tissues was confirmed to be V beta 8.5+ by in situ hybridization and by immunoperoxidase staining. A small population of V beta 10+ cells could also be detected. Furthermore, SGVHD effector T splenocytes depleted of lymphocytes expressing either the TCR-alpha beta or the V beta 8.5 determinant could not adoptively transfer SGVHD. Depletion of T cells expressing the V beta 10 determinant delayed the onset of this autoaggression syndrome. Subset analysis of the autoreactive T cell compartment revealed that the V beta 8.5 determinant was expressed on both CD4+ and CD8+ lymphocytes whereas the V beta 10 determinant was principally expressed on a minor population of CD4+ autoreactive T cells. These data were confirmed by limiting dilution analysis. Additional studies examining the effect of CsA on thymic differentiation revealed that although V beta 8.5 is not normally clonally deleted, there was a pronounced shift in the expression of this determinant between CD4 and CD8 single positive thymocytes, suggesting that CsA may inhibit normal positive selection processes for MHC class I and class II reactive T cells.

Animals↗
PubMed1995

Cytotoxic T cells overcome BCR-ABL-mediated resistance to apoptosis.

Chronic myeloid leukemia is a disease marked by expanded clonal hematopoiesis; it is incurable by chemotherapy or radiation but is cured in a majority of patients receiving bone marrow transplantation from nonidentical sibling donors, an outcome generally attributed to a T cell-mediated graft-versus-leukemia effect. In this report, we examine the effect of the P210BCR-ABL fusion protein of the BCR-ABL oncogene, the molecular hallmark of chronic myelogenous leukemia, on the sensitivity of mouse cell lines to apoptosis induced by chemotherapy, radiation, or activated cytotoxic T lymphocytes (CTLs). We find that, although cells expressing P210BCR-ABL by gene transfer are more resistant than their normal counterparts to apoptosis induced by chemotherapy or radiation, they are equally susceptible to apoptosis induced by alloreactive CTLs. These results show that CTLs overcome BCR-ABL-mediated resistance to apoptosis and, therefore, provide a biological correlation for the success of allogeneic bone marrow transplantation in chronic myelogenous leukemia.

Animals↗
PubMed1994

Graft-versus-host disease: new directions for a persistent problem.

Graft-versus-host disease (GVHD) continues to be a major complication after allogeneic bone marrow transplantation, especially with the increasing use of unrelated and mismatched donors. Recently there has been renewed scientific interest in GVHD because of the increasing appreciation of the complexity of the immune responses seen in GVHD. Two basic aspects of the immune response in GVHD, the immunologic target and the effector mechanisms, are now more completely understood. First, the target of the immune response in GVHD has long been felt to be histocompatibility antigens possessed by the host, but not the donor. Recently, recognition of self antigens in GVHD has been documented, showing that GVHD is more complex than simple alloreactivity. Second, the effector mechanism in GVHD was initially felt to be direct cytotoxicity by alloreactive T cells. It is now recognized that cytokines play a central role in mediating many of the clinical and experimental manifestations of GVHD. The development in these two areas will be reviewed and the implications for clinical transplantation discussed.

Animals↗
PubMed1994

Hepatic and extrahepatic biosynthesis of complement factor C6 in the rat.

The relative contributions of liver and bone marrow (BM) constituents to systemic C6 production were compared in a rat model. Liver grafts were transplanted from C6-sufficient PVG (RT1c) rats (PVG (C+)) to profoundly C6-deficient PVG rats (PVG (C-)). C6 levels were restored to 32% within 24 h and reached more than 80% of that of the PVG (C+) donor within 7 days post-grafting, which indicates that the liver is a primary source of systemic C6 production. When livers were transplanted from PVG (C-) to PVG (C+) rats (n = 3), levels of C6 dropped to 42% of pretransplant levels within 24 h and remained between 30 and 40% for more than 100 days after grafting. To determine the source of extrahepatic C6 production, BM was transplanted from PVG (C+) to PVG (C-) rats after total body irradiation. Levels of C6 increased from undetectable levels to 5% of C6 levels of the donor PVG (C+) rat within 60 days. Replenishing PVG (C-) recipients with BM after treatment of recipients with busulfan, which preferentially allows reconstitution with donor myelomonocyte stem cells, resulted in restoration of C activity. Treatment with cyclophosphamide before BM transplantation, which preferentially allows reconstitution of lymphoid stem cells, did not restore hemolytic C activity in PVG (C-) rats. These results were confirmed directly by the successful restoration of C activity with BM depleted of lymphocytes by counterflow centrifugal elutriation from PVG (C+) rats. These in vivo experiments demonstrate that the liver is a primary, but not the sole, source of C6 in the rat and that extrahepatic sources, such as myelomonocytes, and not lymphoid cells in the BM produce a significant amount of systemic C6 in the rat.

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

Reappraisal of histologic features of the acute cutaneous graft-versus-host reaction based on an allogeneic rodent model.

We employed a rat model of complete major histocompatibility complex-mismatched allogeneic bone marrow transplantation to better characterize the histologic expression of the acute cutaneous graft-versus-host reaction (GVHR), compared with changes due to the preparative regimen. Cyclosporin A abolished the development of this GVHR. Low levels of dyskeratotic cells were present in all groups (allogeneic and syngeneic transplants with and without cyclosporin A) and, alone, were insufficient to diagnose a cutaneous GVHR. A consistent histologic feature of the GVHR was significant lymphoid infiltration of the dermis. The pattern of cytotoxic folliculitis involved follicular epithelium above the entry of sebaceous glands. Immunostain for major histocompatibility complex class II, IA, and IE antigens revealed that dendritic cells within the follicle were limited to this upper region and that lower follicular epithelium did not upregulate expression with evolution of the GVHR. Based on this model, we conclude 1) that the diagnostic scheme for the acute cutaneous GVHR should include lymphoid infiltration of the dermis, 2) that the preparative regimen (including total body irradiation) induces persistent low levels of dyskeratotic cells (two to three cells/linear mm of epidermis), and 3) that the pattern of follicular involvement may relate to the distribution of dendritic cells and to an inability of lower follicular epithelium to upregulate major histocompatibility complex class II antigens.

Animals↗
PubMed1994

Phase I trial of interferon gamma to potentiate cyclosporine-induced graft-versus-host disease in women undergoing autologous bone marrow transplantation for breast cancer.

PURPOSE: We investigated if interferon gamma (IFN-gamma) could augment cyclosporine (CSA)-induced graft-versus-host disease (GVHD) following autologous bone marrow transplant in women with metastatic breast cancer and defined the toxicities of this therapy. PATIENTS AND METHODS: Thirty-six women with advanced breast cancer were treated with CSA 2.5 mg/kg daily for 28 days and IFN-gamma 0.025 mg/m2 subcutaneously (SC) every other day, days 7 to 28 following autologous bone marrow transplantation and monitored for induction and severity of GVHD and toxicity of therapy. RESULTS: GVHD was induced in 56% of patients. The severity of GVHD was greater than in a historic control population treated with CSA alone. Stage III rash was seen in 36% of patients, compared with 3% in the historic control population. Fourteen of 36 patients required therapy with topical corticosteroids and two of 36 required systemic treatment. Only three of 31 historic controls needed topical corticosteroids and no patient was treated systemically. There was no severe visceral GVHD. Hematopoietic recovery was not delayed. There were three toxic deaths. CONCLUSION: CSA-induced GVHD can be safely augmented by IFN-gamma in women treated with high-dose alkylating agents and autologous bone marrow transplantation. There is little evidence of increased toxicity. Evidence of antitumor efficacy awaits further investigation.

Adult↗
PubMed1993

Adoptive transfer of experimental autoimmune dacryoadenitis in susceptible and resistant mice.

Strains of mice with diverse genetic backgrounds were compared for their ability to develop experimental autoimmune dacryoadenitis (EAD) after immunization with a purified lacrimal gland antigen (LG-Ag) in complete Freund's adjuvant. Susceptibility to the induction of EAD was linked to the murine H-2 histocompatibility background. SJL/J mice with the H-2s haplotype were the most susceptible to EAD, developing extensive cellular infiltration of the lacrimal gland, but those with the H-2d haplotype (BALB/c mice) or H-2q haplotype (DBA/J mice) were resistant to EAD, having little or no infiltration of the lacrimal gland. There was no correlation between the development of EAD and either the antibody response or the in vitro lymphocyte proliferative response to LG-Ag. The differences in the induction of EAD observed between susceptible and resistant strains resided in the different capacity of their lymphocytes to transfer disease. Splenocytes from susceptible SJL/J mice sensitized with LG-Ag in CFA could be activated in vitro with LG-Ag to transfer disease to normal syngeneic recipients. The capacity for adoptive transfer was abrogated by treatment with anti-Thy 1.2 antibody plus complement, an indication that T cells are responsible for the transfer of EAD. However, EAD cannot be transferred with the donor cells from resistant mice even after they have been cultured in vitro with LG-Ag. These results suggest that T cells play a major role in the induction of EAD and that variations in susceptibility are under the control of distinct genetically inherited mechanisms that may include active suppression.

Animals↗
PubMed1993

Treatment of experimental autoimmune dacryoadenitis with cyclosporin A.

Experimental autoimmune dacryoadenitis (EAD) was induced in SJL/J mice by a single injection of purified lacrimal gland antigen (LG-Ag) in complete Freund's adjuvant. The disease is characterized by lymphocytic infiltration of the lacrimal gland and production of lacrimal gland-specific antibodies. We examined the effects of cyclosporin A (CsA) on the development and progression of this inflammatory disease. CsA (100 mg/kg/day), given from the time of immunization for 14 days, completely blocked the development of EAD in all treated mice. Both cellular and humoral immune responses to LG-Ag were markedly reduced by the administration of CsA as evidenced by the near absence of lymphocyte proliferative response and the reduced production of circulating anti-LG-Ag antibodies. Delayed CsA treatment beginning on Day 7 after immunization totally abrogated the development of lacrimal histological lesions and lymphocyte proliferative response to LG-Ag. However, serum anti-LG-Ag titers were only marginally decreased in CsA-treated animals. Treatment with CsA was found effective even when daily injections were started 14 days after immunization with LG-Ag. CsA prevented the inflammatory cell response in 5 of 10 mice when the disease was established. The lymphocyte proliferative response to LG-Ag was moderately depressed in CsA-treated animals, but antibody titers were the same as those in the oil-treated control. These studies demonstrate that CsA has a therapeutic effect in this murine model of dacryoadenitis and suggest a critical role for T lymphocytes in the pathogenesis of EAD.

Animals↗
PubMed1993

Cyclosporine-induced syngeneic graft-vs-host disease: prevention of autoaggression by treatment with monoclonal antibodies to T lymphocyte cell surface determinants and to MHC class II antigens.

Administration of cyclosporine (CsA) following syngeneic/autologous bone marrow transplantation (BMT) elicits a T lymphocyte-dependent autoimmune disease resembling graft-vs-host disease (syngeneic GVHD). This autoaggression syndrome appears to be due to the autorecognition of self-MHC class II antigens by CD8+ cytolytic T cells and a CD4+ autoreactive T cell subset. The syngeneic GVHD model was used to assess the effectiveness of treatment with monoclonal antibodies to the alpha/beta T cell receptor (TCR) and the CD4 or CD8 determinants on the prevention of autoimmune disease. Nylon wool nonadherent splenic T cells (50 x 10(6)) from Lewis strain rats with active syngeneic GVHD were adoptively transferred into irradiated (1050 rad syngeneic recipients reconstituted with normal marrow (60 x 10(6) cells). Monoclonal antibody (McAb) to the alpha/beta TCR, the CD4 determinant, or the CD8 determinant was administered to secondary recipients on Days 0, 3, 6, 9, and 12 at a dose of 0.1 ml of ascites fluid. Control animals received normal mouse serum on the same schedule. Animals treated with either saline or normal mouse serum developed syngeneic GVHD within 16-20 days. Comparatively, syngeneic GVHD developed much later in the secondary recipients treated with anti-CD4 McAb (onset of syngeneic GVHD, 28-32 days) and was less severe compared to the control group. On the other hand, the recipients treated with McAb's to the alpha/beta TCR or to the CD8 determinant did not develop syngeneic GVHD (monitored over 10 weeks post-therapy). Peripheral blood lymphocytes from these recipients also were analyzed for T cell subsets by phenotypic analysis. There was a pronounced reduction of the total number of cells expressing the alpha/beta TCR and the CD8 determinant after treatment of the recipients with the McAb's to the alpha/beta TCR and to the CD8 determinant, respectively. Recovery to normal levels began to occur 6 weeks after the last dose of McAb. There was a significant reduction of the CD4+ subset after treatment with anti-CD4 McAb, but it was not long lasting with recovery coinciding with the onset of syngeneic GVHD. Studies were also performed to evaluate McAb therapy of established syngeneic GVHD. The McAb's were found to be largely ineffective due in part to pulmonary toxicity. Furthermore, this model was utilized to evaluate the efficacy of treatment with McAb to the target antigen of syngeneic GVHD. Infusion of McAb to a public determinant on class II MHC molecules prevented or significantly delayed the onset of syngeneic GVHD after adoptive transfer of effector cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

The MA (p15) and p12 regions of the gag gene are sufficient for the pathogenicity of the murine AIDS virus.

Inoculation of the replication-defective retrovirus DEF27 (BM5d), packaged as an amphotropic virus pseudotype, into C57BL/6J mice leads to development of murine AIDS. Disease development showed a long incubation period (20 to 24 weeks), was associated with amplification of the BM5d provirus in splenocytes and lymph nodes, and was independent of the presence of exogenous or endogenous replication-competent helper viruses. However, both the onset of disease and amplification of the defective provirus were significantly enhanced by coinfection with the replication-competent B-cell-tropic ecotropic helper virus BM5e. The part of the BM5d viral genome that was essential for the pathogenicity was determined by making precisely engineered alterations in the reading frame of the gag and pol genes of BM5d proviral DNA and examining the ability of the altered amphotropic BM5d pseudotypes to induce the disease in C57BL/6J mice. The results show that expression of the MA (p15) and p12 regions of the gag gene is sufficient for pathogenicity of the BM5d retrovirus.

Animals↗
PubMed1993

Cyclosporine-induced graft-versus-host disease after autologous bone marrow transplantation for acute myeloid leukemia.

Rodents given cyclosporine (CSP) for several weeks after autologous or syngeneic bone marrow transplantation develop a syndrome that mimics allogeneic graft-versus-host disease (GVHD). Autologous GVHD has also been reported after administration of CSP in patients who have received autologous bone marrow transplantation (ABMT) with untreated marrow for lymphoma or acute myeloid leukemia (AML). Our study was designed to determine whether CSP administration is associated with appearance of autologous GVHD in patients with AML receiving ABMT with 4-hydroperoxycyclophosphamide (4HC)-purged marrow and whether there was a dose-dependent effect of CSP on development of the syndrome. Thirty-three patients with AML (18 in first remission [CR1], 10 in CR2, and 5 in CR3) received intravenous CSP, beginning on the day of ABMT, after a preparative regimen of busulfan and cyclophosphamide and ABMT with 4HC-treated marrow. Skin biopsies were obtained weekly after ABMT or on appearance of rash and were graded for GVH changes. In the first phase of this study, groups of patients received CSP dosages of either 1 mg/kg/day (7 patients), 2.5 mg/kg/day (8 patients), or 3.75 mg/kg/day (6 patients) for 28 days. Sixteen of the 21 patients (76%) developed cutaneous histopathologic grade 2 GVHD at a median of 34 days (range, 14-49) after ABMT, and cutaneous manifestation were present at time of positive biopsy in 11 of the 16 patients. There was no apparent difference in frequency, time to onset, or duration of GVHD among the three CSP dosage groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗