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Biomedical subjects

F T Thomas

Publications and source records attributed to F T Thomas.

At least 37 records · Page 2Linked to original sources
PubMed1994

Further studies of veto activity in rhesus monkey bone marrow in relation to allograft tolerance and chimerism.

Infusing the DR-/dim fraction of bone marrow cells (BMC) from an allogeneic kidney donor into rabbit antithymocyte globulin-treated transplant recipients delivers a tolerogenic signal, leading to functional allograft tolerance in rhesus monkeys without additional drug therapy. Our updated results in an expanded series show a median 131-day graft survival of recipients given DR-/dim donor BMC with a 23% 1-year survival (P < 0.00001 vs. rabbit antithymocyte globulin controls). Removing DRbright cells from donor BMC appeared to have a significant effect (P < 0.05). We have further investigated the tolerogenic mechanism within the experimental framework of the veto hypothesis in this preclinical model. In limiting dilution assays, we demonstrated the donor specificity of clonal inactivation of CTL precursors (CTLp) after in vitro or in vivo exposure to DR-/dim donor BMC, confirming specific tolerance. Additionally, in vitro studies confirmed the allogeneic specificity of CTLp inactivation in 3-cell MLR assays; minimal bystander effects were seen on normal CTLp responses to third party stimulator cells, while CTLp responses to the BMC donor's cells were abrogated in the same cultures. BMC mediating the veto effect were found to be resistant to L-leucyl-L-leucine methyl ester (Leu-leu-OMe), which excluded BMC-mediated cytotoxicity by NK or lymphokine-activated killer cells, CTL, or activated macrophages. In contrast, veto activity was abolished if the BMC were pretreated with either high dose UV-B light irradiation, mitomycin, or gamma-irradiation, indicating that BMC contained a UV-B-sensitive precursor of the veto effector, and that a proliferative step separated the two. Irradiation of DR-/dim donor BMC or administration of cyclophosphamide after infusion of nonirradiated BMC prevented the tolerogenic effect. Only recipients given nonirradiated DR-/dim donor BMC demonstrated PBL chimerism, which associated with functional deletion of antidonor CTLp and duration of graft survival. The Leu-leu-OMe resistance and the other properties of the allogeneic monkey CD3- CD2+ CD8+ BMC subpopulation that exhibits tolerance-promoting activity in vitro and in vivo lead us to postulate that a donor BMC-derived precursor population, possibly a dendritic cell population, may induce allogeneic unresponsiveness in this model.

Animals↗
PubMed1993

15-Deoxyspergualin: a novel immunosuppressive drug with clinical potential.

The studies discussed in this review suggest that DSG is a potent immunosuppressive agent, with at least some of its activity due to its direct effects on macrophages and B cells. The effects of DSG on macrophages include inhibition of IL-1, chemiluminescence, expression of MHC Class I antigen on the surface, and development of MAF. The agent may well interfere with antigen processing and the discovery of its binding to the heat-shock protein 70 may shed some light on this area. The effects of DSG on B lymphocytes include inhibition of surface Ig expression and B cell differentiation. In addition, however, DSG exhibits some effects on both B and T lymphocytes and is markedly active in blocking both the primary and secondary cytotoxic T cell and antibody-producing cell generation. The agent is relatively nontoxic at the doses in which it exerts these marked effects. Thus, an overall assessment of DSG shows that it may provide immune suppression at levels different from those of immunosuppressive agents already available. Advances in human organ transplantation have for the most part occurred stepwise with the introduction of progressively improved techniques of immunosuppression. Tissue-matching, organ preservation, techniques of transplantation, and surgical post-operative care of organ transplant recipients have all improved over the 30 years since organ transplantation began, but have not been the major factors in the improved survival of both patients and grafts seen at the present time. The initial advance in immunosuppression which made the first organ transplants possible was the finding of the immunosuppressive capabilities of azathioprine (Imuran) and the ability to reverse acute rejection crisis with prednisone. Anti-thymocyte or anti-lymphocyte globulin, introduced in 1966, achieved variable results, with some groups reporting excellent patient and graft survival using this agent. Others using different variations of this drug showed no improvement in results. By the mid-1970s, transplant results had improved at a number of units, with graft survivals of kidney and heart recipients in the 70 percent range at 1 to 2 years. No major progress was reported in most units, however, until the introduction in 1978 of cyclosporine. A major effect of cyclosporine was to create a universal improvement in graft survival in all units surveyed around the world with a 70 to 75 percent one-year cadaver kidney graft survival, representing the basic standard for clinical results.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Kidney allograft tolerance in primates without chronic immunosuppression--the role of veto cells.

Posttransplant infusion of specific donor bone marrow cells into ATG-treated recipients promotes long survival of allografts in the absence of immunosuppressive drug therapy. DBMC infusion also inhibits antidonor CTL activation in allograft recipients, a trend analogous to the veto phenomenon. The present studies investigated a hypothesis that veto activity in DBMC is involved in the induction of donor-specific unresponsiveness in rhesus monkey kidney transplant recipients given ATG and DBM. Normal monkey BMC were fractionated into subpopulations by depletion with mAbs and immunomagnetic beads. The unfractionated BMC and BMC subsets were tested for veto activity in in vitro MLR-induced CTL and for in vivo tolerance-promoting activity in ATG-treated monkey kidney transplant recipients. In MLR-induced CTL assays, BMC specifically suppressed CTL activity to PBL from the BMC donor. The suppression was mediated by a small population of BMC that expressed a CD2+, CD8+, CD16+, DR-, CD3-, CD38- phenotype. Results of in vivo studies showed a striking correlation with the in vitro results. ATG-treated recipients given either DR- DBMC or DR- CD3- DBMC infusions had significantly prolonged graft survival and a 40-50% incidence of long survivors over 150 days (P less than 0.001 vs. ATG controls). In contrast, in recipients given CD2- DBMC or DR- CD16- DBMC infusions, the tolerance-promoting effect of DBMC was absent, and there were no long-term survivors. The results also showed an association between long survival and suppressed in vivo antidonor CTL activity. Thus acute rejection and in vivo and in vitro antidonor CTL responses were suppressed by a minor subpopulation of DBMC with similar phenotypic markers. We suggest that a veto mechanism may control the induction phase of allograft tolerance in this model, providing a critical period of CTL silence to allow development of host immunoregulatory mechanisms necessary for maintaining graft tolerance.

Animals↗
PubMed1991

Muscle insulin resistance in uremic humans: glucose transport, glucose transporters, and insulin receptors.

To determine the cellular basis for insulin resistance observed in patients with uremia, we investigated insulin action in vivo and in vitro using skeletal muscle obtained from patients with chronic renal failure. Uremic subjects had significantly reduced rates of insulin-stimulated glucose disposal, as determined by a 3-h intravenous glucose tolerance test and using the hyperinsulinemic euglycemic clamp technique. Hepatic glucose production was similar before (control, 76.2 +/- 6.3 vs. uremic, 74.2 +/- 6.9 mg.kg-1.min-1) and during insulin infusion at 40 mU.m-2.min-1 (control, -60.9 +/- 6.6 vs. uremic, -53.9 +/- 6.3 mg.kg-1.min-1). In incubated human skeletal muscle fiber strips, basal 2-deoxy-D-glucose transport was unchanged in uremic subjects compared with controls. However, the increase in insulin-stimulated glucose transport was significantly reduced by 50% in muscles from uremic patients (P = 0.012). In partially purified insulin receptors prepared from skeletal muscle, 125I-labeled insulin binding, beta-subunit receptor autophosphorylation, and tyrosine kinase activity were all unchanged in uremic subjects. The abundance of insulin-sensitive (muscle/fat, GLUT-4) glucose transporter protein measured by Western blot using Mab 1F8 or polyclonal antisera was similar in muscles of control and uremic patients. These findings suggest that the insulin resistance observed in skeletal muscle of uremic patients cannot be attributed to defects in insulin receptor function or depletion of the GLUT-4 glucose transporter protein. An alternative step in insulin-dependent activation of the glucose transport process may be involved.

Adult↗
PubMed1991

Immunobiology of the xenograft response: xenograft rejection in immunodeficient animals.

These studies provide insight into the immunobiology of xenograft rejection. They suggest that xenograft rejection involves T-cell phenomena, although the ability of the nude rat (functionally known to be T-cell deficient) to reject the vascularized xenograft normally is striking and clearly indicates a need for future studies of this phenomenon. These studies strongly suggest a role for NK and K cell-type activity in xenograft rejection, although they also indicate this immune function is only an ancillary one and that xenograft rejection will eventually occur despite deficiencies in these systems. These studies are most provocative in showing a failure of efficiency of skin graft rejection in the purest model of B-cell deficiency, the XID model. Since these results are obtained with the so-called secondarily vascularized xenograft (skin grafts) it is not possible to exclude the role of B-cell and B-cell-associated phenomena in vascularized organ grafts without further studies.

Animals↗
PubMed1990

Donor-specific tolerance permits burn allografting without increased sepsis.

Early excision and allografting of massive burns is beneficial. However, chronic immunosuppression, utilized to prolong allograft survival, increases the potential risk of infection. We have previously shown long-term skin allograft survival in mice with a 30% total body surface area (TBSA) burn by inducing donor-specific tolerance (DST) using only perigrafting administration of antithymocyte globulin (ATG) and donor bone marrow (DBM). Chronic immunosuppression is avoided. This study tests whether induction of DST compromises host resistance to infection. Resistance to a septic challenge created by cecal ligation and puncture (CLP) 10 days after a 30% TBSA burn was investigated in the following groups of mice: [table: see text] Positive blood cultures were documented for 97% of mortalities. Burn excision and grafting significantly (P less than or equal to 0.05) decreased mortality. No increased mortality was seen in allografted mice receiving ATG or ATG and DBM compared to isografted mice receiving no immunosuppression. These studies suggest that skin allografting with DST may permit the benefits of burn excision without the risks of infection seen with chronic immunosuppression.

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