Search PubMed⌕ Search

Biomedical subjects

A D Hess

Publications and source records attributed to A D Hess.

At least 91 records · Page 5Linked to original sources
PubMed1988

Characterization of the natural suppressor cell population in adult rat bone marrow.

Natural suppressor cell activity (NSCA) has been ascribed to a subset of cells present in human and murine hematopoietic tissues which can suppress a variety of lymphocyte responses without MHC restriction. We investigated NSCA in lymphocyte-depleted rat bone marrow (BM) which is used as a model for prevention of graft vs host disease (GVHD) following allogeneic BM transplantation (BMT). The T-cell depleted fraction obtained after elutriation contained higher levels of NSCA than the unseparated BM. Further separation of this graft fraction by discontinuous Percoll gradient centrifugation revealed high levels of radiosensitive NSCA in the low density (less than 1.070) fraction which represented 0.5% of the original BM population. These cells were of blast morphology, stained intensely with a dansylated derivative of cyclosporine A (dans CsA) and weakly expressed macrophage/granulocyte antigens and non-specific esterase (NSE). These cells were initially non-adherent but proliferated in culture to produce intensely NSE positive, adherent, phagocytic cells of macrophage morphology. We conclude that the highly suppressive, radiosensitive cell present in rat BM may be of early progenitor or monocyte lineage. The grafting of natural suppressor (NS) cells and progenitor cells may affect graft/host immunoregulation and their characterization may provide insight into GVH biology and graft rejection.

Animals↗
PubMed1988

Cellular immune status in retinitis pigmentosa.

Previous reports have suggested a role of cellular and/or humoral immunity in retinitis pigmentosa. Because of the controversial nature of many of these reports, the authors undertook a detailed investigation of cellular and humoral immunity in a well-characterized group of 47 persons with retinitis pigmentosa of various heritability patterns and a similar number of age- and sex-matched controls. The authors found two changes in lymphocyte subsets. Retinitis pigmentosa patients had significantly elevated Leu 3A-positive lymphocytes (CD4 or T-helper cells) and significantly fewer Leu 2A-positive lymphocytes (CD8 or T-suppressor cells) than controls, although the total numbers of T cells did not differ between the two groups. A small but significant number of retinitis pigmentosa patients expressed interleukin 2 (IL-2) antigens on their lymphocytes as compared with none of the controls. The authors saw no differences between the retinitis pigmentosa and control groups in the inducibility and secretion of gamma-interferon or IL-2. Concentrations of immunoglobulins G, A, and M did not differ between the two groups. The link between immune system alterations and the retinitis pigmentosa process remains tenuous.

Adolescent↗
PubMed1988

Acute graft-versus-host disease: clinical characteristics in the cyclosporine era.

Graft-versus-host disease (GVHD) remains the major problem in allogeneic bone marrow transplantation. GVHD has limited the use of this technique to HLA-matched donor recipient pairs. Thus, only a quarter of patients who ultimately may have benefited from bone marrow transplantation are currently eligible. Even in matched patient recipient pairs, GVHD accounts for approximately 40% of the deaths following allogeneic bone marrow transplants. One of the major challenges for transplantation is to derive better strategies to prevent and treat GVHD while retaining the allogeneic benefit of graft-versus-leukemia. Current pharmacologic approaches have used cyclosporine, usually in combination with other drugs. More experimental approaches have removed lymphocytes from the marrow grafts. With either approach, maintaining the anti-leukemic benefit of an allogeneic transplant (i.e., immunologic attack of the leukemia resulting in a lower relapse rate), will need to be maintained if that approach will ultimately prove to be useful.

Acute Disease↗
PubMed1988

Transfer of cyclosporine-associated syngeneic graft-versus-host disease by thymocytes. Resemblance to chronic graft-versus-host disease.

Syngeneic rat radiation chimeras treated transiently with cyclosporine (CsA) often develop a GVHD-like syndrome after discontinuing the drug. CsA also causes medullary involution and loss of medullary epithelium in the thymus. Chronic graft-versus-host disease (GVHD), a late occurring syndrome following bone marrow transplantation with many features of autoimmune diseases, is thought by many to result from a thymic deficiency leading to a failure to develop specific tolerance for the host. A direct connection between a thymic deficiency and chronic GVHD was tested by transferring thymocytes from CsA-treated syngeneic Lewis chimeras into irradiated Lewis secondary recipients. Nine of 10 of these recipients had evidence of chronic GVHD in skin biopsies taken at 3 weeks posttransplant or in the autopsies at 5 weeks. Changes included characteristic lichen planuslike infiltrates and sclerodermalike changes in the skin, characteristic infiltrates and myositis of the tongue, often chronic hepatitis with bile duct injury, and interstitial and ductal infiltrates in the serous salivary glands. Immunoperoxidase stains of the skin and tongue infiltrates showed a marked predominance of W3/25+:OX8- lymphocytes. The hair follicles had increased expression of Ia antigen. The thymus in the secondary recipient had variable thymocyte reconstitution of the cortex and a mild to marked reduction in the relative size of the medulla. Stains for cytokeratin showed a moderate to marked reduction of cortical epithelium and marked to total loss of the medullary epithelium. These studies demonstrate that the features of post-CsA syngeneic GVHD resembling chronic GVHD result from an abnormal thymic microenvironment. They also provide additional evidence linking a thymus deficiency with chronic GVHD.

Animals↗
PubMed1988

Cyclosporine-induced cell-mediated injury of the thymic medullary epithelium.

Cyclosporine (CsA) can induce prolonged tolerance to alloantigens, but it requires an intact thymus. In normal rats, CsA causes a rapid but reversible ablation of the thymic medulla with an associated loss of the Hassall's corpuscles and apparent maturation arrest of the thymocytes. We have tested the hypothesis that CsA induces a cell-mediated lysis of the medullary epithelium. Normal rats were treated with CsA (15 mg/kg) or vehicle. The thymocytes were then adoptively transferred into syngeneic target rats, purged of thymocytes by recent total-body irradiation. After 4-48 hr, the target animals were sacrificed. The target thymi showed increased lymphocytic exocytosis of the Hassall's corpuscles with OX-8+ (CD8+) T lymphocytes (OX-19+, OX-44+) and associated epithelial cell injury. Compared to recipients of control thymocytes, ultrastructural evaluation showed broad-based and point contact between lymphocytes and adjacent medullary epithelium with increased epithelial cell injury. The results support a cell-mediated injury to the Hassall's corpuscles in CsA-treated animals.

Animals↗
PubMed1988

Inverse correlation of cyclosporine binding with sensitivity and resistance.

The primary effects of CsA on human lymphocyte responses in vitro appear to be the inhibition of IL-2 production and the inhibition of cytotoxic T cell activation. Induction of suppressor T cell activity is resistant to the effects of CsA. These data imply two distinct subsets of lymphocytes: CsA-resistant and CsA-sensitive. The current studies used a bioactive, dansylated derivative of CsA (dans-CsA), which is fluorescent, to assess binding of CsA at the single-cell level by flow cytometry. The results demonstrate that two populations of cells can be distinguished based on differential staining with dans CsA--a weakly staining subset and a population that binds intensely. Both subsets consist of CD4 (helper) and CD8 (cytotoxic/suppressor) T lymphocytes. Functional analysis revealed that the weakly staining subset consists of IL-2-producing T cells and precursor cytotoxic T lymphocytes. On the other hand, the intensely staining subset includes T cells that suppress in an antigen-specific manner after activation with alloantigen. Further studies showed that the weakly staining subset is markedly sensitive to the immunosuppressive effects of CsA in a PHA stimulation assay, while the intensely binding population is markedly resistant, requiring 10- to 100-fold more CsA to inhibit the PHA response. These studies suggest that sensitivity and resistance to CsA is inversely correlated with binding.

Antigens, Differentiation↗
PubMed1988

Cyclosporine-induced pseudo-graft-versus-host disease in the early post-cyclosporine period.

Cyclosporine-induced pseudo-graft-versus-host disease (CIPGVHD) in syngeneic or autologous rat marrow chimeras has clinical and histologic features closely resembling classic graft-versus-host disease in the allogeneic chimera. We describe here the pathology and immunopathology of the usual target tissues in CIPGVHD developing in the first week following CsA (early group). The findings are constrasted to the CIPGVHD developing during the second week post-CsA (later group). Six of 9 rats in the early group had acute-type CIPGVHD in the tongue, skin, liver, intestines, and mainstem bronchi. In general, the lymphocytic infiltrates in these tissues were in intimate contact with injured epithelial cells. The intestines had multiple apoptotic lesions. Class II antigen was prominent in the tongue mucosa, but only patchy expression was evident in 2 skin biopsies. All of the lymphocytes infiltrating the mucosa were CD8+(OX-8)/CD4-(W3/25) T cells (OX-19+). Most of the lymphocytes in the lamina propria expressed CD4 as well as CD8 markers, suggesting coexpression. In the later group, 6 of 7 rats had chronic-type CIPGVHD (1 with acute and chronic) while 1 rat had no GVHD (P = .02, Fisher's exact test compared with the early group). These animals had features characteristic of established chronic GVHD in the skin, tongue, liver, intestines, and salivary glands. Fibrosis of the dermis and lamina propria was prominent in the skin and tongue. Submucosal fibrosis was increased in the small intestine. The salivary glands had an interstitial infiltrate and fibrosis with loss of ducts and glands. Class II antigen was prominent in the epidermis of the tongue and skin of all rats. The number of lymphocytes infiltrating the mucosa of the tongue was considerably smaller than seen in the early group. More than 90% of these cells were T cells, as detected by OX-19, and expressed both CD4 and CD8 markers. While most lamina propria lymphocytes expressed the CD4 antigen, there were significantly fewer CD8+ cells, consistent with increased numbers of CD8-/CD4+ helper-phenotype cells. The observations indicate that immediately post-CsA, the CIPGVHD is primarily acute, with epithelial infiltrates of CD8+/CD4- T cells and lamina propria infiltrates that include double-labeled cells consistent with immature thymocytes. There is a rapid transition to established chronic-type CIPGVHD by the second week. The residual mucosal infiltrate is now dominated by double-labeled T cells or thymocytes while the lamina propria infiltrate has more mature helper-phenotype T cells. Induced RT1.B/D antigen could be important in the pathogenesis of the peripheral tissue manifestations.

Acute Disease↗
PubMed1988

Thalidomide for treatment of graft-versus-host disease.

We have used thalidomide in a rat major MHC mismatch model of graft-versus-host disease (GVHD). When given prophylactically, most animals do not develop GVHD and those developing mild GVHD respond to continued therapy. Treatment of established acute GVHD, likewise, was successful. In both prophylactic and therapeutic administration, animals did not develop GVHD after drug cessation. Animals were shown to be stable chimeras by acceptance of donor strain skin grafts and mixed lymphocyte cultures (no response to donor or recipient strain while responding to third party strain). Treatment of chronic GVHD in this model has shown thalidomide to be better tolerated and more successful than cyclosporine (CSA) or prednisone plus azathioprine. The mechanism of action of thalidomide has been explored using a fluorescent thalidomide derivative. These studies have shown striking similarities between thalidomide and CSA. Both drugs appear to allow the development of antigen specific suppressor cells while inhibiting the development of precursor cytotoxic cells. Because of these encouraging results, we have begun a phase I/II trial of thalidomide in refractory GVHD. The preliminary results are encouraging.

Animals↗
PubMed1988

Separation of rat bone marrow cells by counterflow centrifugal elutriation: a model for studying the effects of lymphocyte depletion.

We have developed a simple three flow-rate, fixed rotor speed, counterflow centrifugal elutriation (CCE) procedure that permits the isolation of an engraftable lymphocyte-depleted (greater than 98%) fraction from ACI rat bone marrow. The different cell fractions were characterized by morphology, alloreactivity in mixed lymphocyte culture and limiting dilution analysis, colony-forming capacity, and their capacity to reconstitute hematopoiesis and effect a graft-versus-host reaction in lethally irradiated allogeneic hosts. After CCE fractionation of ACI rat marrow, transplantation of the lymphocyte-depleted marrow fraction resulted in sustained engraftment without evidence of clinical or histologic acute graft-versus-host disease (GVHD). CCE fractionation of rat bone marrow may be a useful preclinical model for studying lympho-hematopoietic and immune reconstitution after transplantation with lymphocyte-depleted donor marrow, as well as for studying the role of lymphocyte subpopulations on engraftment, acute GVHD, and leukemia relapse in syngeneic and allogeneic bone marrow transplantation.

Animals↗