Biomedical subjects

A D Hess

Publications and source records attributed to A D Hess.

At least 73 records · Page 4Linked to original sources

PubMed1990

Age-related factors in cyclosporine-induced syngeneic graft-versus-host disease: regulatory role of marrow-derived T lymphocytes.

The present studies have evaluated the effect of age on the induction of syngeneic graft-versus-host disease (SGVHD) after syngeneic bone marrow transplantation (BMT) and cyclosporine (CsA) therapy. The results clearly document an inverse correlation of age with the incidence of SGVHD. Virtually a 100% incidence of SGVHD occurs in Lewis rats when syngeneic BMT and CsA therapy are started when the animals are 4 wk of age. Thereafter, there is a dramatic decline in the incidence of SGVHD with the increasing age of the animals. Although the age of the recipient was important, the most significant effect was the age of the marrow donor. Marrow from animals 6 mo of age was virtually incapable of eliciting SGVHD after BMT and CsA therapy. Furthermore, mixing the marrow from mature and immature animals resulted in a decreased incidence of SGVHD, implicating a regulatory effect present in the marrow from older rats. This regulatory effect was due to the presence of mature T cells in the marrow from animals 6 mo of age. Despite the fact that marrow from young animals possesses mature T lymphocytes, this regulatory activity was absent, suggesting that the host resistance mediated by T lymphocytes develops as the animal ages. These data further implicate the importance of a host resistance mechanism in preventing the induction of SGVHD with CsA, which appears to be mediated by the clonal inactivation of autoreactive cells.

Aging↗

PubMed1990

Activation of T-cells by bryostatins: induction of the IL-2 receptor gene transcription and down-modulation of surface receptors.

Bryostatins are macrocyclic lactones isolated from the marine bryozoan Bugula neritina. They are currently evaluated for putative antineoplastic activity. Bryostatins bind and activate protein kinase C (PK-C), the cellular receptor for the phorbol ester, and elicit PK-D-dependent cellular functions. Such functions include the expression of the interleukin-2 receptor (IL-2R). Northern blot hybridization with a human IL-2R and an IL-2 cDNA showed that bryostatin 1 (bryo 1), like the phorbol ester, PMA, activates the IL-2R gene. Activation with bryo 1 or PMA in the presence of a calcium ionophore, A23187, increased IL-2 message. These findings indicate that calcium mobilization is necessary for bryo 1 or PMA induced IL-2 gene expression. Unlike PMA, bryo 1 did not cause a vigorous proliferative response of T-lymphocytes unless A23187 was added to the cultures. A bryostatin congener, bryo 13, was inactive in the above assays. Short-term treatment of T-cells with bryo 1 and PMA resulted in an equivalent down-regulation of surface CD3 and CD4 receptors without affecting the CD8 receptor. Bryo 1 or PMA mediated expression of surface IL-2R and T-cell proliferation induced by bryo 1 or PMA were sensitive to inhibition by the PK-C antagonists staurosporine (Sts) and H-7. In contrast, CD4 and CD3 down-regulation were resistant to H-7, but could be blocked by Sts, although the Sts concentration required to block bryo 1 or PMA-induced down-modulation was 2.5-fold higher than required to inhibit IL-2R expression and T-cell proliferation. These results indicate that bryostatins activate T-cell through PK-C.

Antigens, Surface↗

PubMed1990

The thymus and prolonged administration of cyclosporine. Irreversible immunopathologic changes associated with autologous pseudo-graft-versus-host disease.

Previous studies have demonstrated that short-term administration of cyclosporine leads to immunopathologic changes in the thymus, including medullary involution, loss of Hassall's corpuscles, and decreased class II antigen expression. Generally these changes are rapidly reversible. In rats treated with mediastinal irradiation, however, these changes are irreversible and usually associated with autologous or syngeneic graft-vs.-host disease (pseudo-GVHD). This study describes the immunopathology of the thymus after long-term administration of CsA (7 mg/kg/day, up to 140 days) and monitors the recovery post-CsA. The medulla was markedly involuted at the end of CsA, regardless of duration. The relative size of the medulla showed good recovery. Long-term CsA, however, profoundly delayed or prevented the recovery of Hassall's corpuscles and normal expression of class II antigen. The epithelial cells in Hassall's corpuscles totally disappeared at the end of CsA administration. Following 7 or 28 days of CsA, the Hassall's corpuscles recovered within one month. After 70 days CsA, recovery was delayed until the second month, while after 140 days, Hassall's corpuscles were not present even 2 months post-CsA. Class II antigen was decreased in the subcapsular and juxtamedullary regions at 140 days as well as 1 and 2 months post-CsA. Paralleling the thymic immunopathology, acute and chronic pseudo-GVHD were observed in the skin, tongue, liver, intestines, lacrimal glands, bronchi, and intestines following long-term CsA.

Animals↗

PubMed1990

Using elutriation to engineer bone marrow allografts.

We have used elutriation to deplete lymphocytes from the marrow allografts of 64 patients to date. The first phase I trial (1 x 10(6) lymphocytes/kg IBW) was designed to test the procedure for potential toxicities, most notably, graft failure. Study 2 (1 x 10(6) lymphocytes/kg, no CsA) was expected to reduce potential toxicity incurred from long term immunoprophylaxis while study 3 was aimed at reducing the incidence of GVHD by further reducing lymphocyte dose (5 x 10(5)/kg). Graft lymphocyte dose was based on morphologic determination and was subsequently confirmed by limiting dilution analysis and flow cytometry. Although grafts were standardized solely by lymphocyte dose, the product was more uniform than the original harvested BM with respect to other cell populations. Nearly all study I (n = 40) and study III (n = 20) patients engrafted with a median time to ANC greater than 500/ul of 19 days. Three of the 4 patients consecutively enrolled in study II failed to engraft, thus terminating the trial. While a moderate proportion of study I patients had AGVHD (44%) with attendant morbidity, only 20% of study III patients were found to have mild AGVHD (less than or equal to stage I). To date, this cohort has no organ or chronic GVHD and no GVHD-associated morbidity. Median follow-up times for patients in studies I and III are 27 and 11 months, respectively. Overall actuarial survival (n = 60) is 42% at 38 months (38% study I, 80% study III). Good prognosis study I patients experienced 45% actuarial survival versus 9% in the poor prognostic group. While lymphocyte depletion has been effective in reducing the incidence and severity of AGVHD, new strategies are needed to address the issue of disease relapse. As with other methods, lymphocyte depletion by elutriation caused an increased rate of leukemia relapse. The actuarial probability of remaining in remission for recipients of elutriated marrow containing 1 x 10(6) and 5 x 10(5) lymphocytes/kg, respectively, were 60% and 46% at 16 months. Elutriation provides a rapid, reproducible and flexible methodology for graft manipulation which has been effective in reducing the incidence and severity of AGVHD. However, if lymphocyte depletion is to fulfill its promise as a means of reducing the overall morbidity of allogeneic BMT, new strategies may be needed to address the issue of relapse. These may include changes in marrow ablative therapy and post-graft immunosuppression. Equally as important may be the ability to further manipulate accessory cells and lymphoid populations presently excluded from the graft.

Adult↗

PubMed1990

Elutriation of bone marrow delineates two distinct natural suppressor cell populations.

It appears that part of the confusion surrounding the lineage of NS cells could be due, in part, to the presence of more than one cell population in normal BM. Whether other cell populations exist in other organ compartments, or can be induced, is presently unknown. This is of particular interest in allogeneic BMT where various lymphocyte depletion techniques have been employed to reduce the incidence of AGVHD. When CCE is used for depletion, the NS lymphocyte component is entirely removed. Since the incidence of AGVHD is significantly reduced with CCE lymphocyte-depleted rat and human BM, it appears that this subpopulation need not be present to abrogate AGVHD. Quite surprisingly, preliminary studies in rats indicates that this lymphocyte subpopulation may actually induce acute syngeneic GVHD (Fischer et al., 1989). That a cell(s) in the clonogenic compartment has the ability to suppress or down-regulate a variety of immune responses is not altogether surprising. This cell is better thought of as an auto-regulatory cell which has the ability to control the cellular interactions in its immediate micro-environment. Indeed, R/O NSCA can be augmented by GM-CSF, IL-3, and CsA (NoGa et al., 1988a). In vitro, this cell differentiates into the mono-myeloid series using a variety of stimulatory agents and can acquire tumoricidal activity. The ability to express NSCA is lost however, being present only during a brief window of early maturation. Only IL-3 can sustain NSCA in culture.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗

PubMed1989

Successful in vitro graft-versus-tumor effect against an Ia-bearing tumor using cyclosporine-induced syngeneic graft-versus-host disease in the rat.

Lethally irradiated LouM rats reconstituted with syngeneic bone marrow and then treated with cyclosporine (CsA) for 40 consecutive days following transplant developed a graft-v-host disease (GVHD)-like syndrome after CsA cessation. This model of GVHD was used to define and characterize a graft-v-tumor (GVT) effect against a syngeneic plasmacytoma CRL1662 cell line which expresses class II major histocompatibility (MHC) antigen (Ia). Nylon wool-nonadherent spleen cells from animals who developed syngeneic GVHD were capable of significant lysis against chromium-labeled tumor target cells in a four-hour chromium released cell mediated lympholysis assay; maximum lysis occurred five days following cessation of CsA when clinical signs first appeared. Cytolytic activity declined to baseline as GVHD symptoms resolved. Fractionation of splenocytes into lymphocyte subsets demonstrated that cytolytic lymphocytes (CTLs) of the OX8 phenotype (non-helper T) were capable of significant lysis against tumor target cells. Lysis of tumor cells was blocked by preincubation with monoclonal antibodies (MoAb) specific for the rat anti-class II MHC antigen but not with MoAb against class I. Incubation of tumor cells with gamma-interferon increased expression of tumor class II MHC antigens and significantly increased their susceptibility to lysis by nylon wool-nonadherent splenocytes from animals with syngeneic GVHD. These studies have demonstrated an in vitro GVT of syngeneic GVHD against an Ia-bearing tumor; the effector cell is a CTL of the OX8 phenotype specific for the class II MHC antigen.

Animals↗

PubMed1989

Induction of graft-versus-host disease after autologous bone marrow transplantation.

To induce graft-versus-host disease (GvHD) in patients undergoing autologous bone marrow transplantation (BMT), five consecutive patients with non-Hodgkin lymphoma or Hodgkin's disease in resistant relapse were treated with cyclophosphamide and total body irradiation or busulphan and cyclophosphamide, followed by autologous BMT. The patients received cyclosporin 1 mg/kg per day intravenously for 28 days after BMT. Histologically proven grade II acute GvHD of the skin developed in all the patients at a median of 11 days (range 9-13) after BMT. One patient died and the GvHD resolved in 1-3 weeks in the four remaining patients--spontaneously in two and with corticosteroid treatment in two. Lymphocytes from one patient obtained at the time of GvHD were cytotoxic for the patient's own pretransplant lymphocytes. Cytotoxicity was blocked by antibodies directed against class II histocompatibility (HLA-DR or Ia) antigens. Cyclosporin-induced GvHD after autologous BMT resembles mild GvHD after allogeneic grafting. This syndrome appears to be mediated by autoreactive Ia-specific lymphocytes.

Acute Disease↗

PubMed1989

Requirements for the induction and adoptive transfer of cyclosporine-induced syngeneic graft-versus-host disease.

These studies further delineate the requirements for the establishment and transfer of SGVHD. We show that (a) two mechanisms distinguishable by radiation and drug sensitivities exist, (b) lethal irradiation correlates with a 100% incidence in the induction of SGVHD, whereas (c) both sublethal or lethal irradiation and cytoxan therapy are effective in ablating the host autoregulatory system in order to transfer autoreactivity, (d) unfractionated as well as nylon wool-nonadherent splenocytes effectively inhibit the transfer of autoimmunity, and (e) OX19 depletion of that population, however, destroys the autoregulatory effect present in normal splenocytes. To demonstrate complete inhibition of immune reactivity, twice the number of unfractionated splenocytes from normal animals was required for every splenocyte from autoimmune donors. Last, the infusion of effector splenocytes on 4, 7, and 14 d after transplantation correlates to a decrease from 100%, 70 to 0% incidence of SGVHD, thus emulating the incidence obtained in a pretransplant rat within 2 wk. These findings further clarify the immunobiological complexity of SGVHD and suggest that since autoregulatory cells already exist in normal animals that CsA-induced autoimmunity is a reflection of not an induced reactivity specific to one therapeutic reagent but the uncoupling of normal immunologic mechanisms essential in controlling autoimmunity.

Animals↗

PubMed1989