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Biomedical subjects

A D Hess

Publications and source records attributed to A D Hess.

At least 19 recordsLinked to original sources
PubMed2003

Enhancement of cyclosporin A-induced autologous graft-versus-host disease after peripheral blood stem cell transplantation by utilizing selected CD34(+) cells.

Although autologous graft-versus-host disease (GVHD) can be induced by administration of cyclosporin A (CsA) after peripheral blood stem cell transplantation (PBSCT), the incidence appears to be remarkably lower compared to the incidence after bone marrow transplantation. The reduced incidence of autologous GVHD after PBSCT may be attributed to peripheral regulatory cells that are transferred with the stem cell inoculum. To determine whether transplantation of CD34-selected peripheral blood stem cells (PBSCs) leads to potentiation of autologous GVHD, five patients with malignant lymphoma were transplanted with CD34-selected PBSCs, followed by administration of CsA and interferon (IFN)-gamma. Inducibility of autologous GVHD and autocytotoxic activities of peripheral blood mononuclear cells (PBMCs) after transplantation were assessed. All patients demonstrated prompt hematologic recovery. Cytotoxic activity of PBMCs against autologous lymphocytes was detectable in four of four patients analyzed during a limited period from days 14 to 34 post-transplant. An erythematous rash compatible with GVHD, confirmed by skin biopsy, developed in three of five patients. One of the three patients developed not only skin, but also gut and liver GVHD. Transplantation of the CD34-selected stem cell graft that does not accompany transfusion of regulatory cells may potentiate the inducibility of autologous GVHD by the administration of CsA and IFN-gamma.

Antigens, CD34↗
PubMed2001

Characterization of the T-cell repertoire in autologous graft-versus-host disease (GVHD): evidence for the involvement of antigen-driven T-cell response in the development of autologous GVHD.

Administration of cyclosporine A (CsA) after autologous stem cell transplantation elicits an autoimmune syndrome with pathology similar to graft-versus-host disease (GVHD). This syndrome, termed autologous GVHD, is associated with the appearance of autoreactive T cells directed at major histocompatibility class (MHC) class II antigens. In the rat model of autologous GVHD, clonal analysis reveals that the effector T cells are highly conserved and recognize a peptide from the invariant chain peptide presented by MHC class II. Although human autologous GVHD effector T cells share a similar phenotypic specificity, clonality of the response in humans has not been determined. To examine the human effector T-cell response, the T-cell repertoire of peripheral blood lymphocytes was assessed by complementarity-determining region 3 (CDR3) size distribution analysis and T-cell clonotype analysis in 26 patients treated with CsA after transplantation. Autologous GVHD developed in 3 of 4 patients with human leukocyte antigen (HLA)-DRB1*0701, and clonal expansions of beta-chain variable region (BV)16(+) T cells were shared. Clonal expansions within BV15(+) and BV22(+) T cells were also detected in 4 of 6 patients with HLA-DRB1*1501 and in 3 of 4 patients with HLA-DRB1*0401, respectively. Sequencing of BV16 cDNA for which the CDR3 size pattern exhibited apparent clone predominance revealed an identical CDR3 peptide sequence in 2 different patients, one with HLA-DRB1*0701 and the other with HLA-DRB1*1502. These findings indicate that the discrete antigen-driven expansion of T cells is involved in autologous GVHD. (Blood. 2001;98:868-876)

Adult↗
PubMed2001

Autoimmune-mediated vasculopathy.

The use of the immunosuppressive drug cyclosporine A (CsA) in solid organ transplantation can be associated with the development of vasculopathy as part of the complex immune response involved in chronic rejection, including autoimmune recognition. Although CsA can directly affect endothelial cells, this drug alters the T cell repertoire promoting autoimmune recognition. The present studies evaluated the ability of CsA-induced autoreactive T cells to mediate vascular lesions in syngeneic heart grafts. Graft vasculopathy developed in syngeneic heart grafts following either the primary induction of autoimmunity with CsA or the adoptive transfer of CsA-induced autoreactive T cells. Initially, an inflammatory response occurred in the medial wall of the small arterial vessels, accompanied by a perivascular lymphocytic infiltrate (including a lymphocytic infiltrate into the myocardium), followed by progression of vascular disease with endothelial cell proliferation. The development and progression of vascular disease correlated with the cytokine profile of the infiltrating lymphocytes with type 1 cytokines detected early and type 2 cytokines detected as the disease progressed. Initiation of this response correlated with upregulation of the target antigen recognized by the CsA-induced autoreactive T cells, the MHC class II-invariant chain peptide complex. This antigen complex, when upregulated on endothelial cells by interferon, allowed effective targeting by the autoreactive T lymphocytes. Strategies to inhibit the upregulation of MHC class II antigens by treatment of the recipients with chloroquine truncated the disease process. The results of these studies suggest that CsA-induced autoreactive mechanisms can contribute to the development of graft vasculopathy.

Adoptive Transfer↗
PubMed2001

The N-terminal flanking region of the invariant chain peptide augments the immunogenicity of a cryptic "self" epitope from a tumor-associated antigen.

The N-terminal flanking region of the invariant chain peptide termed CLIP appears to have superagonistic properties interacting with the T cell receptor and the MHC class II molecule at or near the binding site for the bacterial superantigen Staphylococcal enterotoxin B (SEB). The present studies explored the hypothesis that the N-terminal segment of CLIP can augment the immunogenicity of cryptic "self" tumor-associated antigens. A chimeric construct of an MHC class II binding peptide from the c-erb oncogene (Her-2/neu) containing the N-terminal flanking region of CLIP elicited potent antitumor activity against a Her-2/neu-positive tumor in a rat model system. Comparatively, the unmodified parent peptide was ineffective. The induction of effective antitumor immunity, however, required presentation of the chimeric peptide construct on irradiated tumor cells or the peptide construct in concert with a Her-2/neu MHC class I-restricted peptide from Her-2/neu. As revealed by adoptive transfer studies, effective protective antitumor immunity in this setting required the CD4 T helper subset. Additionally, in vitro analysis revealed that immunization with the parent peptide resulted in a weak immune response to the unmodified peptide consisting of both type 1 (IL-2, IFN-gamma) and type 2 (IL-4, IL-10) cytokine-producing cells analyzed by RT-PCR (qualitative and quantitative) and by limiting dilution assay. Comparatively, immunization with the chimeric construct elicited a potent immune response to the parent peptide with predominantly type 1 cytokine-producing cells. Taken together, the results suggest that immunization with the chimeric Her-2/neu peptide induced protective antitumor immunity. Associated with this immunization strategy was the enhancement of a type 1 cytokine response.

Animals↗
PubMed2000

Complexity of effector mechanisms in cyclosporine-induced syngeneic graft-versus-host disease.

Administration of the immunosuppressive drug cyclosporine after syngeneic or autologous bone marrow transplantation elicits a T-lymphocyte-dependent autoimmune syndrome similar to graft-versus-host disease (GVHD). The onset of this autoaggression syndrome, termed syngeneic GVHD, is associated with the development of a highly restricted repertoire of CD8+ autoreactive T cells that recognize a peptide from the invariant chain, termed CLIP, presented by major histocompatibility complex (MHC) class II molecules. Clonal analysis reveals 2 distinct subsets of autoreactive T cells defined by their activation requirement for either the N-terminal or the C-terminal flanking regions of CLIP and by their cytokine profile. The studies here reveal that the autoreactive T-cell clones requiring the N-terminal flanking region of CLIP produce type 1 cytokines (interferon [IFN]-gamma, interleukin [IL]-2, and tumor necrosis factor-alpha). In contrast, the autoreactive T-cell clones that require the C-terminal flanking region of CLIP produce type 2 cytokines (IL-4, IL-10, transforming growth factor-beta). As assessed in a local graft-versus-host reaction assay, the N-terminal flanking-restricted clones mediate changes consistent with acute GVHD, whereas the clones responsive to the C-terminal flanking region do not. Moreover, the autoreactive T-cell clones restricted by the C-terminal flanking region of CLIP ameliorate the pathogenic potential of the cells responsive to the N-terminal flanking region of CLIP. The mechanism accounting for this regulatory affect appears to be the downregulation of mRNA message for type 1 cytokines (IFN-gamma and IL-2). The C-terminal-restricted autoreactive T-cell clones, however, could manifest disease with dermal changes similar to those seen in chronic syngeneic GVHD, provided that IFN-gamma was present. Consistent with these observations was the demonstration that type 1 cytokines are preferentially detected during the acute phase of syngeneic GVHD, whereas type 2 cytokines dominate during the chronic phase. The results suggest that acute and chronic syngeneic GVHD is mediated by distinct autoreactive T cells, which are separated by their fine specificity for the CLIP-MHC class II complex and by their cytokine profiles.

Animals↗
PubMed2000

Autologous graft-versus-host disease induction in advanced breast cancer: role of peripheral blood progenitor cells.

The purpose of the present study was to investigate the impact of the use of peripheral blood progenitor cells (PBPCs) on the induction of autologous graft-versus-host disease (GVHD) in patients with advanced breast cancer. 14 women with stage IIIB and 36 women with stage IV breast cancer received cyclosporine (CsA) 2.5 mg kg-1 i.v. daily, d 0-28, and interferon-gamma (IFNg) 0.025 mg/m2 s.c. qod, d7-28, following PBPC-T +/- bone marrow transplantation (BMT). Preceding high-dose chemotherapy consisted of cyclophosphamide 6 g/m2 and thiotepa 800 mg/m2. Histologically proven > or = grade II cutaneous GVHD was induced in18/50 (36%) of patients and was independent of the source of haematopoietic support. In vitro studies showed that post-transplant, 76% of patients had developed auto-cytotoxicity against their own pre-transplant PHA-lymphoblasts. A significant correlation between the occurrence of GVHD > or = grade II and cytolysis was observed in the NK cell-line K562 and the T47D breast cancer cell-line. With a median follow-up of 2(1/2) years, the overall survival (OS) is 58%, the disease-free survival (DFS) 26%, both independent of the development of GVHD and similar to what has been observed in other studies on high-dose chemotherapy in advanced breast cancer. It therefore remains unclear whether the induction of autologous GVHD with the occurrence of auto-cytotoxic lymphocytes can result in an anti-tumour effect in this group of patients.

Adult↗
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↗
PubMed1998

Characterization of the pathogenic autoreactive T cells in cyclosporine-induced syngeneic graft-versus-host disease.

Administration of the immunosuppressive drug cyclosporine after syngeneic bone marrow transplantation paradoxically elicits a systemic autoimmune syndrome resembling graft-vs-host disease (GVHD). This syndrome, termed syngeneic GVHD, is associated with the development of CD8+ cytolytic T lymphocytes that promiscuously recognize MHC class II molecules in association with a peptide from the invariant chain (CLIP). Clonal analysis reveals a major subset of cells that are pathogenic and require the N-terminal flanking region of CLIP for activation, while there is a minor subset of nonpathogenic T cells that require the C-terminal flanking region. The present studies show that pathogenic T cells produce type 1 cytokines (IL-2; IFN-gamma), while the nonpathogenic clones produce type 2 cytokines (IL-4; IL-10). Moreover, the repertoire of the pathogenic T cells is highly conserved with respect to V beta and V alpha TCR gene expression. The vast majority of clones express V beta8.5 (12/12) and V alpha11 (11/12). Although a limited number was evaluated, the nonpathogenic clones have only a V alpha restriction. Sequence analysis of the pathogenic T cell clones reveals a marked heterogeneity in the complementarity-determining region 3 domain and differential J region gene expression for both TCR alpha- and beta-chains. Evaluation of the specificity of these clones suggests that the functional interaction between the N-terminal flanking region of CLIP (defined by the amino acid sequence -KPVSP-) and the V region of the TCR is critical, allowing effective target cell recognition and tissue destruction in syngeneic GVHD.

Amino Acid Sequence↗
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↗
PubMed1998

CD34+ stem cell augmentation of elutriated allogeneic bone marrow grafts: results of a phase II clinical trial of engraftment and graft-versus-host disease prophylaxis in high-risk hematologic malignancies.

Although T cell depletion of allografts used in BMT has reduced GVHD, it has been associated with inferior engraftment and an increased risk of relapse. We have found that T cell depletion by counterflow centrifugal elutriation (CCE) also results in depletion of CD34+ stem cells. In order to determine if the discarded CD34+ cells would improve engraftment, we undertook a phase II trial of allogeneic BMT in which 110 patients (median age 43) with a variety of hematologic malignancies received CD34+ stem cell augmented, elutriated marrow grafts. The T cell-depleted grafts were tightly controlled and contained a mean of 4.3 x 10(7) mononuclear cells/kg, 3.3 x 10(6) CD34+ cells/kg, 1.5 x 10(5) CFU-GM/kg and 5.5 x 10(5) CD3+ T cells/kg. Median time to engraftment of granulocytes (>500/microl) was 16 days and of platelets (>50000/microl) was 25 days, comparable to that seen with unmanipulated marrow. No mixed hematopoietic chimerism was observed that was not associated with disease relapse. The four patients (3.6%) who failed to engraft were all at high risk because of prior donor transfusions or underlying marrow disorders. The incidence of GVHD was dependent on the duration of cyclosporin A (CsA) immunosuppression. In patients who received CsA for > or = 80 days, the incidence of clinically significant acute GVHD (>stage 1) and extensive, chronic GVHD was 5% and 11%, respectively. Peritransplant (< or = 100 day post-BMT) mortality for this group of patients was 15%. Event-free survival in selected subsets of patients compared favorably to previous studies in which patients received unmanipulated marrow allografts.

Adolescent↗
PubMed1998

CD34 augmentation improves allogeneic T cell-depleted bone marrow engraftment.

T cell depletion (TCD) performed by elutriation has decreased the incidence of acute and chronic graft-versus-host disease (GvHD) following bone marrow transplantation (BMT). However, as with all forms of TCD, patients may experience graft failure (10%), delayed engraftment, and mixed chimerism. Because 66%-75% of the CD34+ cells coseparate with the small lymphocytes, which are removed by elutriation, we designed a phase I trial in HLA-identical siblings to determine if the readdition of these previously lost small CD34+ cells would improve elutriation's engraftment kinetics. CD34+ cells were isolated from the small cell fraction of 10 consecutive donor grafts and infused into the recipients along with the TCD graft. The positively selected product had a mean T cell content of 1.2 x 10(5)/kg and was 80% CD34+, doubling the CD34+ content of the graft. All patients engrafted promptly with a median time to 500 neutrophils/mm3, untransfused 50,000 platelets/mm3, and discharge from the hospital of 19 (range 10-25), 24 (14-52), and 24 (18-29) days, respectively. Acute GvHD occurred in 2 patients, and no patient had chronic GvHD. Augmenting stem cell dose may be an efficient and safe alternative for overcoming TCD-associated delayed engraftment and graft failure, rather than increasing immunosuppression.

Adult↗
PubMed1997

Specificity of effector T lymphocytes in autologous graft-versus-host disease: role of the major histocompatibility complex class II invariant chain peptide.

Administration of the immunosuppressive drug cyclosporine after autologous bone marrow transplantation induces a systemic autoimmune syndrome resembling graft-versus-host disease (GVHD). This syndrome termed autologous GVHD has significant antitumor activity. Associated with autologous GVHD is the development of T lymphocytes that recognize major histocompatibility complex (MHC) class II determinants, including self. The present studies attempted to characterize and define the molecular specificity of the effector T lymphocytes in autologous GVHD induced in patients with metastatic breast cancer. The results suggest that the effector cells associated with human autologous GVHD are CD8+ T lymphocytes expressing the alpha/beta T-cell receptor. Additional studies show that the effector T cells recognize MHC class II antigens in association with a peptide from the invariant chain (CLIP). Pretreatment of autologous lymphoblast target cells with anti-CLIP antibody completely blocked lysis mediated by autologous GVHD effector T cells. On the other hand, force loading this peptide markedly enhanced the susceptibility of the target cells to recognition by the autoreactive T cells. The recognition of the MHC class II CLIP complex may account for the novel specificity of the effector T cells associated with human autologous GVHD. Moreover, identification of the target peptide may allow for the development of novel immunotherapeutic strategies to enhance the antitumor efficacy of autologous GVHD.

Adolescent↗
PubMed1997

Immunobiology and immunotherapeutic implications of syngeneic/autologous graft-versus-host disease.

Administration of the immunosuppressive drug cyclosporine (CsA) after syngeneic/autologous bone marrow transplantation (BMT) elicits an autoimmune syndrome with pathology virtually identical to graft-vs-host disease (GVHD). The induction of this syndrome, termed syngeneic/autologous GVHD, is a two-tiered process requiring both the active inhibition of thymic-dependent clonal deletion and the elimination of mature T cells that have an immunoregulatory effect. Eradication of the peripheral immunoregulatory compartment by the preparative regimen provides a permissive environment for the activation of the syngeneic/autologous GVHD effector T cells. Although the repertoire of autoreactive effector T lymphocytes is highly conserved, these T cells promiscuously recognize MHC class II determinants. This novel specificity of the autoreactive lymphocytes appears to be dependent on the peptide derived from the MHC class II invariant chain. Recent studies also suggest that these promiscuous autoreactive T cells can effectively target and eliminate MHC class II-expressing tumor cells. Administration of cytokines that upregulate the target antigen or expand the effector population can potentiate the antitumor activity of syngeneic/autologous GVHD. Although the induction of syngeneic/autologous GVHD is an untoward effect of CsA immunosuppression, mobilization of these autoimmune mechanisms provides a promising immunotherapeutic approach for certain neoplastic diseases.

Animals↗
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↗