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M Sykes

Publications and source records attributed to M Sykes.

At least 181 records · Page 10Linked to original sources
PubMed1988

Mechanism of protection from graft-vs-host disease in murine mixed allogeneic chimeras. I. Development of a null cell population suppressive of cell-mediated lympholysis responses and derived from the syngeneic bone marrow component.

Splenocyte populations from whole body-irradiated recipients of mixed T cell-depleted (TCD) syngeneic and allogeneic (complete H-2 disparity) bone marrow, or of TCD syngeneic marrow alone, contain cells with the ability to suppress the generation of cell-mediated lympholysis responses in vitro. This activity, which is present by 8 days after bone marrow transplantation and persists for several weeks, has been analyzed for possible veto-like or other specificity. Although reproducible patterns of suppression were observed, depending both on host strain and on the genetic combination of the response examined, the overall suppression in vitro most closely resembles that which has been ascribed to "natural suppressor" cells in other systems. The suppression appears to be mediated by a non-T cell, non-B cell, nonadherent, asialo GM1-negative population. Cold target inhibition and CTL activity of chimeric cells have been ruled out as factors contributing to the observed suppression. Significantly, in mixed chimeras, suppression was found to be mediated exclusively by cells which were syngeneic to the recipient in both recipient strains tested. The rapid development of this suppressive activity may explain the resistance to graft-vs-host disease conferred on whole body-irradiated mice by the addition of TCD syngeneic marrow to an allogeneic graft-vs-host disease-producing inoculum.

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PubMed1988

Mechanisms of suppression in mixed allogeneic chimeras.

Cells with the ability to suppress cytotoxic T lymphocyte generation are found in the spleens of whole-body-irradiated (WBI) mixed allogeneic and syngeneic bone marrow transplant recipients in the early weeks after BMT. Previous studies have indicated that suppression is mediated by "null cells" similar to natural suppressor (NS) cells (1), and have ruled out several possible trivial explanations for the suppressive effect. We report here the results of additional experiments designed to assess possible mechanisms of suppression. We compared the cell populations after 5 days' incubation of cultures containing normal responding splenocytes plus irradiated allogeneic stimulator cells, with or without a cocultured suppressive chimeric splenocyte population. The data indicate that total viable cell yields are only slightly reduced, if at all, in suppressed cultures, but that the proportion of T cells is markedly reduced as measured at the end of the incubation period. Splenocytes from early BMT recipients do not appear to proliferate during the suppression of a mixed lymphocyte culture, and such populations represent only 15% of cells at the end of the 5-day incubation period. Suppression is strongest when the suppressive population is added at the initiation of MLC, and is lost if addition is delayed beyond day 3. Suppression can be overcome by T cell growth factor (TCGF)--and, to a lesser extent, by recombinant IL-2 (rIL-2), although resting suppressive populations do not consume appreciable amounts of these lymphokines. These results therefore suggest that suppression in MLC may occur primarily during the induction of helper T lymphocytes.

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PubMed1988

Achieving alloengraftment without graft-versus-host disease: approaches using mixed allogeneic bone marrow transplantation.

Two opposing immunologically-mediated phenomena currently limit the success of bone marrow transplantation (BMT) in HLA-identical situations and impede the application of this therapeutic modality across MHC barriers. These phenomena are: (1) the response of T cells within the donor marrow allograft to recipient alloantigen, resulting in graft-versus-host disease (GVHD) with its attendant morbidity and mortality; and (2) the response of recipient cells which have survived the ablative conditioning regimen against alloantigen borne by the donor marrow allograft, leading to failure of alloengraftment. While T cell depletion of donor marrow has successfully reduced the incidence of severe GVHD, this reduction has been associated with an increased incidence of failure of alloengraftment. In this communication we review several recent approaches being studied in animal models in our laboratory to avoid such undesirable effects of host-anti-donor and donor-anti-host alloaggression. The first approach is based on the observation that administration of T cell-depleted (TCD) syngeneic bone marrow (BM) appears to limit GVHD while still permitting engraftment by co-administered non-TCD allogeneic BM. This anti-GVH effect of TCD syngeneic marrow can be enhanced by delaying the administration of allogeneic BM by 8 days following whole body irradiation and syngeneic BMT. Evidence that natural suppressor cells derived from syngeneic marrow may be responsible for this phenomenon is reviewed. We also present evidence for the existence of a non-stem cell bone marrow subpopulation, distinct from those T cells which cause GVHD, which is capable of increasing levels of allogeneic chimerism.(ABSTRACT TRUNCATED AT 250 WORDS)

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PubMed1987

HDL clearance and receptor-mediated catabolism of LDL are reduced in hypothyroid rats.

Hypercholesterolemia associated with hypothyroidism is due partly to increased plasma LDL and partly to increased HDL cholesterol concentrations. The increase in LDL cholesterol has been shown to be secondary to reduced plasma clearance of LDL. To determine which catabolic route was thyroid dependent, the present study examined the effects of hypothyroidism on the receptor-mediated pathway and the 'receptor-independent' pathway of LDL metabolism. Wistar rats (327 +/- 22 g; mean +/- SD) were made hypothyroid by feeding propylthiouracil (0.1%, w/w) and rat 131I-LDL (rLDL; d = 1.019-1.050) and 125I-methylated-LDL (rLDL-CH3) were simultaneously injected i.v. after which the rates of clearance of labelled LDL in plasma were determined over 0-54 h. Total LDL and 'receptor-independent' clearances were represented by clearance of 131I-rLDL and 125I-rLDL-CH3 respectively and the difference between the two represented high affinity receptor-mediated clearance. The data were analyzed using Matthews' model and the fractional catabolic rates (FCR) were calculated. The FCR of rLDL clearance via the receptor-mediated pathway was 0.1042 +/- 0.0112 pools/h (n = 6) in controls vs. 0.0613 +/- 0.0079 pools/h (n = 6) in hypothyroid animals (P less than 0.01). The FCR via the 'receptor-independent' pathway was 0.0642 +/- 0.0040 pools/h (n = 6) in controls vs. 0.0561 +/- 0.0036 pools/h (n = 6) in hypothyroid animals (not significant). The plasma HDL cholesterol concentration was also increased in hypothyroid rats (70.4 +/- 6.7 mg/dl) compared to control (53.3 +/- 3.1 mg/dl) (P less than 0.025).(ABSTRACT TRUNCATED AT 250 WORDS)

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PubMedDate not supplied

Tolerance induction for xenotransplantation.

The transplantation of donor hematopoietic tissue prior to organ xenografting has the potential to induce lasting T cell tolerance and, possibly, tolerance of natural antibody-producing B cells. However, the development of specific and nontoxic methods of overcoming the immunologic and physiologic barriers to xenogeneic marrow engraftment is a major challenge that must be met before this goal can be achieved. A greater understanding of the species specificity of molecular interactions important for hematopoiesis and cell homing is a first step toward transcending these physiologic barriers. Perhaps most promising is the potential associated with the use of nonprimate xenogeneic donors genetically engineered to make donor tissues more readily capable of surviving and, in the case of hematopoietic cells, competing with host tissues for survival in a human environment.

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PubMedDate not supplied

Multiple mixed chimeras: reconstitution of lethally irradiated mice with syngeneic plus allogeneic bone marrow from multiple strains.

Reconstitution of lethally irradiated B10 mice with a mixture of 5 x 10(6) B10 plus 15 x 10(6) B10.D2 T-cell-depleted (TCD) bone marrow (BM) cells has previously been shown to produce stable, mixed chimeras which are specifically tolerant to donor skin grafts; the inclusion of TCD syngeneic marrow in the inoculum leads to improved immunocompetence in the resulting chimeras. In order to determine whether this method of transplant tolerance induction could be extended to multiple simultaneous allogeneic donors, we have investigated the engraftment capacity of combinations containing syngeneic and more than one allogeneic source of bone marrow. B10 mice were lethally irradiated and reconstituted with a mixture of (B10 + B10.D2 + B10.BR) or (B10 + B10.RIII + B10.BR) TCD BM. Analysis of each group of animals by flow microfluorometry provided evidence for stable multiple mixed chimerism in the majority of animals. All animals which exhibited such multiple chimerism were also tolerant of skin grafts from both allogeneic donors and promptly rejected fourth party skin grafts. An attempt to produce chimerism with TCD marrow from 5 allogeneic plus syngeneic BM cells was less successful. When animals were given non-TCD allogeneic BM from 2 allogeneic donors along with TCD syngeneic BM, they reconstituted as fully allogeneic chimeras in which one or the other allogeneic donor prevailed. These results indicate that (1) multiple allogeneic donor BM cells can engraft simultaneously in the mixed marrow model, but there may be a limit to the number of marrow strains which can repopulate a single animal; (2) multiple allogeneic engraftment confers transplantation tolerance to multiple donors; and (3) TCD is essential to permit multiple mixed chimerism to develop.

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