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Biomedical subjects

A D Hess

Publications and source records attributed to A D Hess.

At least 127 records · Page 7Linked to original sources
PubMed1985

An in vitro predictive test for graft versus host disease in patients with genotypic HLA-identical bone marrow transplants.

Acute graft versus host disease remains a major cause of morbidity and mortality in allogeneic bone marrow transplantation. To date, no clinically useful test has been reported that will predict the occurrence of graft versus host disease in genotypic HLA-identical donor-recipient pairs. We have developed a skin-explant model using donor lymphocytes that have been sensitized against recipient lymphocytes in vitro and cocultured with the recipient's skin. Histologic changes compatible with acute graft versus host disease are found in the positive explants. To date 32 patients have been tested in a prospective manner. Among the 18 recipient-donor pairs that were positive, 16 patients were found to have histologic Grade 2 or higher graft versus host disease of the skin on biopsy. Among the 14 negative pairs, only 3 patients had histologic Grade 2 or higher graft versus host disease of the skin on biopsy. Thus, the model has a sensitivity of 84 per cent and a specificity of 85 per cent, and is a significant predictor of the histologic occurrence of graft versus host disease (P less than 0.0005 by chi-square test). The test may be useful in the selection of donors for bone marrow transplantation and in the planning of prophylaxis against graft versus host disease.

Adolescent↗
PubMed1985

Cyclosporin A binding to calmodulin: a possible site of action on T lymphocytes.

Cyclosporin A, a potent immunosuppressive agent, has been widely used to treat patients with solid organ transplants. Although its precise mechanism of action is unknown, it appears to inhibit subsets of T lymphocytes at an early stage in cell activation. Fluorescent, fully active derivatives of cyclosporin A and calmodulin, a protein that binds calcium and is therefore essential to normal cell function, were utilized to demonstrate that cyclosporin A binds to calmodulin. Flow cytometry showed that the calmodulin inhibitors R24571 and W-7 competitively inhibited binding of cyclosporin A to cloned T lymphocytes. Cyclosporin A inhibited the calmodulin-dependent activation of phosphodiesterase in a dose-dependent manner. Binding of cyclosporin A to calmodulin may prevent the latter's role in the activation of the second messengers and enzymes required for effective cell proliferation and function in the immune response.

Binding, Competitive↗
PubMed1985

Development of graft-vs.-host disease-like syndrome in cyclosporine-treated rats after syngeneic bone marrow transplantation. I. Development of cytotoxic T lymphocytes with apparent polyclonal anti-Ia specificity, including autoreactivity.

Lethally irradiated rats reconstituted with syngeneic bone marrow and treated with cyclosporine (CsA) for 40 d develop a graft-vs.-host disease-like syndrome (GVHD) after CsA therapy. We attempted to assess the development of autoreactivity in these animals. Results revealed that a majority of the animals with syngeneic GVHD develop autocytotoxic T lymphocytes of the OX8 phenotype. In addition to reactivity with self, these cells were capable of lysing appropriate target cells from a variety of different rat strains. The target antigens appeared to be class II major histocompatibility antigens, because lysis could be effectively blocked by an anti-Ia monoclonal antibody. Cold target inhibition studies indicated that one effector cell was capable of lysing various target cells, and provided evidence against a polyclonal activation of multiple anti-Ia-reactive cells. These results suggested that the anti-class II autoreactive cell associated with syngeneic GVHD either recognizes a common class II determinant ("public" epitope) shared by multiple strains of rats, or was polyspecific with respect to "private" class II determinants.

Animals↗
PubMed1985

Effect of interleukin 2 on the immunosuppressive action of cyclosporine.

The influence of exogenous interleukin 2 (IL-2) on the immunosuppressive effect of cyclosporine in the mixed lymphocyte response (MLR) was examined. Results show that addition of exogenous IL-2 to a MLR containing graded doses of CsA (0.01-2.5 micrograms/ml) restored a normal proliferative response to alloantigens. In contrast, the effect of exogenous IL-2 on the induction of cytotoxic lymphocytes in primary MLR in the presence of CsA was variable. At the highest doses of CsA (0.5-2.5 micrograms/ml), no cytotoxic T cell activity could be detected, regardless of the presence of exogenous IL-2. However, at a lower dose of CsA (0.1 microgram/ml) that routinely resulted in the total inhibition of cytotoxic T cell induction, addition of exogenous IL-2 resulted in significant levels of detectable cytotoxic T cell activity. The effect of time-sequential addition of CsA or CsA-plus-exogenous-IL-2 on the proliferative and CML responses in MLR was also examined. Results show that addition of CsA to ongoing primary MLR cultures within the first 48-96 hr of culture results in the significant inhibition of the proliferative and CML response in MLR. Addition of CsA-plus-exogenous-IL-2 to ongoing cultures resulted in no significant inhibition of the proliferative response. In contrast, addition of CsA-plus-exogenous-IL-2 within the first 4 hr of culture did not overcome the immunosuppressive effect of CsA. At 18 hr of culture addition of CsA resulted in complete suppression of the CML response, whereas the addition of CsA-plus-IL-2 resulted in significant levels of cytotoxicity. Thereafter addition of CsA-plus-IL-2 resulted in enhanced levels of cytotoxic T cell activity compared with cultures receiving CsA alone. Taken together, our results suggest that: (1) exogenous IL-2 can overcome the immunosuppressive effect of CsA on the proliferative response in MLR to alloantigens; (2) at high levels of CsA, IL-2 cannot overcome the immunosuppressive effect of CsA on the induction of cytotoxic T-lymphocytes; (3) there are doses of CsA at least in vitro, that allow for the activation of the cytotoxic T cell, presumably with the acquisition of a receptor for IL-2 but without the clonal amplification due to inhibition of IL-2 production; and (4) time-sequential studies revealed that the development of responsiveness to IL-2 by the precursor cytotoxic T cell occurs 4-18 hr after exposure to the stimulating alloantigen with clonal expansion if IL-2 is present.

Animals↗
PubMed1985

Effect of cyclosporin and interleukin-2 on the restoration of in vitro immune responses to cytomegalovirus.

Previous studies have shown that cyclosporin (CSA) inhibits lymphoproliferation to cytomegalovirus (CMV)-infected, glutaraldehyde-fixed, and irradiated fibroblasts (CMVFFx) in vitro. Generation of cytotoxic cell activity is impaired in cultures with CSA, but the induction of suppressor cells is not. In the present studies we tested the ability of interleukin-2 (IL-2) and supernatants of lymphocytes stimulated by CMVFFx with or without CSA (1 microgram/ml) to restore functional activities of lymphocytes from primary cultures treated or not treated with CSA. IL-2 significantly enhanced lymphoproliferation, cell-mediated cytotoxicity to CMV-infected fibroblasts (CMVF), natural killer cell activity, and the activity of cells capable of suppressing the response of fresh autologous cells to CMVFFx of cells derived from control and CSA-treated primary cultures. IL-2 was found in day-2 supernatants of control cultures but not CSA-treated cultures. Day-2 control supernatants were capable of significantly enhancing proliferation and suppressor cell activity but were less efficient at restoring cytotoxic cell function. Day-2 supernatants from CSA-treated cultures were not able to enhance lymphoproliferation or cytotoxic cell function but did induce significant levels of suppressor cell activity. The results indicate the presence of different functional mediators in the culture supernatants. The ability of IL-2 to restore lymphocyte effector functions against a clinically important virus may have important therapeutic implications in the treatment of this viral infection in immunodeficiency diseases and in the restoration of immune competence after transplantation.

Cell Line↗
PubMed1983

Effect of several antiviral agents on human lymphocyte functions and marrow progenitor cell proliferation.

Toxicity to hematopoiesis and lymphocytic function are major considerations in the clinical applicability of antiviral agents. We have examined the toxicities of five antiviral agents showing activity against herpesviruses: vidarabine, acyclovir, (E)-5-(2-bromovinyl)-2'-deoxyuridine, trifluorothymidine, and (S)-9-(2,3-dihydroxypropyl)adenine. The drugs were tested in vitro for inhibition of herpes simplex virus type 1 and human cytomegalovirus replication, effects on marrow progenitor cell growth, effects on lymphocyte responses to mitogen and alloantigen stimulation, and effects on several lymphocyte cytotoxic responses. In general, lymphocyte proliferative responses were inhibited by the various drugs at lower concentrations than were cytotoxic activities. Acyclovir and (E)-5-(2-bromovinyl)-2'-deoxyuridine were the least toxic drugs tested, with antiviral indices exceeding 10,000. Vidarabine and trifluorothymidine were more toxic, with antiviral indices generally between 10 and 100. (S)-9-(2,3-dihydroxypropyl)-adenine was the most toxic, with several antiviral indices between 1 and 10.

Antiviral Agents↗
PubMed1983

Effect of cyclosporine on the response of normal human lymphocytes to cytomegalovirus in vitro.

Lymphocytes from healthy volunteers seropositive for cytomegalovirus (CMV) demonstrated strong lymphoproliferative responses to CMV-infected and glutaraldehyde-fixed foreskin fibroblasts (CMVFFx) when cocultured for 6 days. Addition of the immunosuppressive drug cyclosporine (CsA) to the cultures resulted in a 10-fold reduction (P less than 0.001) in counts per minute of [3H]thymidine uptake. The proliferative response to noninfected fixed fibroblasts was also reduced 10-fold. Kinetic studies showed an inhibition of the lymphoproliferative response and not an alteration in the time course kinetics in CsA-treated cultures. Cytotoxicity to CMV-infected and unfixed fibroblasts by lymphocytes primed by CMVFFx in the presence of 0.5 micrograms of CsA per ml was significantly reduced (P less than 0.01) as compared with untreated cultures but remained significantly above background level (P less than 0.01). The cytotoxic response was still present but reduced at concentrations of greater than or equal to 1.0 micrograms/ml. Cytotoxicity to noninfected fibroblasts by CMVFFx-primed lymphocytes could be eliminated by as little as 0.5 micrograms of CsA per ml. Stimulation of lymphocytes by CMVFFx but not by noninfected fixed fibroblasts resulted in the in vitro generation of suppressor cells. CsA at a final concentration of 1.0 or 2.5 micrograms/ml did not significantly impair the induction of cells capable of suppressing the lymphoproliferative response of fresh autologous mononuclear cells to CMVFFx. The findings described above may have important clinical implications in that a degree of protective immunity to CMV-infected cells is maintained even in the presence of CsA.

Cell Division↗
PubMed1983

Cyclosporin-A to prevent graft-versus-host disease: a pilot study in 22 patients receiving allogeneic marrow transplants.

Cyclosporin-A (CsA) was given to 22 patients who received allogeneic bone marrow transplants as therapy for aplastic anemia and hematologic malignancies. The drug was given daily for 180 days starting with the day of marrow infusion. Engraftment was not impaired and myelotoxicity was not observed. Cutaneous graft-versus-host disease (GVHD) developed in five patients and all either spontaneously resolved or promptly responded to therapy with steroids. Five patients developed systemic GVHD and all responded to therapy with steroids, but only two survived. Interstitial pneumonia was seen in six patients and was fatal in all of them. Liver function abnormalities were seen in 14 patients but could not positively be correlated with CsA administration. Renal function abnormalities were seen in 17 patients. Amphotericin-B therapy contributed significantly to the renal failure. Serum levels of CsA, measured by radioimmunoassay, could not be correlated with the presence of liver or renal function abnormalities. Overall survival so far has been 50.0%. Second malignancies were not observed, but one patient relapsed with leukemia at 343 days.

Adolescent↗
PubMed1982

Suppressor cells in transplantation tolerance. III. The role of antigen in the maintenance of transplantation tolerance.

Suppressor cells, which in an alloantigen-specific manner inhibit proliferation of donor cells to host antigens in a mixed lymphocyte culture and adoptively transfer the suppression of graft-versus-host disease (GVHD), undergo a gradual clonal reduction in long-term, allogeneic, histoincompatible rat radiation chimeras until they can no longer be measured in an in vitro suppressor cell assay. When lymphohematopoietic cells from these chimeras are transferred into lethally irradiated secondary recipients of original donor strain, the suppressor cells, now in a target antigen-free environment, undergo a further clonal reduction. After "parking" for 120 days, the chimeric cells are specifically tolerant to original host antigens, but cannot adoptively transfer suppression of GVHD. When chimeric cells, parked for 120 days in secondary recipients of original donor strain, are stimulated with original host-type antigen repeatedly during or once at the end of the parking period, the suppressor cell clone is expanded, suppressor cells can be identified in vitro, and suppression of GVHD can adoptively be transferred to tertiary recipients.

Animals↗
PubMed1982

4-hydroperoxycyclophosphamide: a model for eliminating residual human tumour cells and T-lymphocytes from the bone marrow graft.

Autologous bone marrow transplantation in acute leukaemia carries the risk of relapse from reinfusion of tumour cells present in marrow collected in remission and cryopreserved. An effective method for clearing marrow of tumour cells is required for a successful outcome. In the animal model 4-hydroperoxycyclophosphamide (4-HC) has proved to be effective in eliminating tumour cells from an autologous marrow graft. In the present studies, the in vitro effect of short- and long-term marrow cell incubation with 4-HC on haemopoietic stem cells was investigated to determine the maximum concentration of 4-HC that can be used for in vitro incubation without destroying the capacity of the marrow to effect complete haematological recovery as judged by residual CFUc content. However, loss of CFUc may not necessarily parallel survival of pluripotential stem cells. 4-HC was also shown to be effective against peripheral T-lymphocytes. Its possible therapeutic use in preventing or ameliorating graft-versus-host disease in allogeneic marrow grafts by preincubation with 4-HC prior to transplantation is discussed.

Bone Marrow Transplantation↗
PubMed1982

Cyclosporin A and the immune response to transplantation antigens.

Cyclosporin A (CsA) is a promising new immunosuppressive agent with considerable clinical potential. In addition to its ability to prolong allografts and possibly induce transplantation tolerance, this agent appears capable of selectively affecting different T lymphocyte subpopulations. Thus, Cyclosporin A may not only be a useful drug in clinical transplantation, but it may also become an important immunologic probe allowing the dissection of complex cellular interactions involved in the immune response.

Animals↗
PubMed1982

Effect of cyclosporin A on human lymphocyte responses in vitro. III. CsA inhibits the production of T lymphocyte growth factors in secondary mixed lymphocyte responses but does not inhibit the response of primed lymphocytes to TCGF.

The mechanism whereby Cyclosporin A (CsA) inhibits secondary mixed lymphocyte responses was assessed. CsA added to secondary MLR cultures inhibited proliferation and induction of cytolytic lymphocyte activity. This inhibition was found to be associated with the inhibition of T lymphocyte stimulating growth factor(s) (TCGF) production in the supernatants of secondary MLR cultures. As little as 1.0 micrograms/ml of CsA added to secondary MLR cultures resulted in no measurable TCGF activity. In contrast, moderate doses of CsA (1.0, 2.5 micrograms/ml), which completely inhibited the secondary MLR response to alloantigen, did not inhibit the proliferative and CML response of alloantigen-primed lymphocytes to these stimulating growth factors. Even at high doses of CsA (20 micrograms/ml), substantial levels of proliferation (50% of control response) and CML induction (60% of control response) were observed when the primed cells were exposed to secondary MLR supernatants containing TCGF activity. It was concluded that inhibition of secondary mixed lymphocyte responses by CsA may be due in part to the inhibition of TCGF production rather than the inhibition of the effect of TCGF on mature cytotoxic T lymphocytes.

Cyclosporins↗
PubMed1981

Suppressor cells in transplantation tolerance. I. Suppressor cells in the mechanism of tolerance in radiation chimeras.

Histoincompatible-complete radiation chimeras, after resolving acute graft-versus-host disease (GVHD), establish specific tolerance to host and donor alloantigens. This tolerance can be perturbed with immunosuppressive agents and infusions of small numbers of donor-type cells, with infusions of massive numbers of donor-type cells, or with infusions of a small number of donor-type cells, that were sensitized against host antigens prior to transfer. These chimeras possess T lymphocytes in the spleen that specifically suppress donor to host mixed lymphocyte reactions and adoptively transfer suppression of GVHD to secondary hosts. Nylon-wool fractionation of chimeric spleen cells restores the response of chimeric lymphocytes to host alloantigens, suggesting that transplantation tolerance is not attributable to clonal deletion but the activity of nylon-wool-adherent T suppressor spleen cells.

Animals↗