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Biomedical subjects

B M Hall

Publications and source records attributed to B M Hall.

At least 55 records · Page 3Linked to original sources
PubMed1990

Specific unresponsiveness in rats with prolonged cardiac allograft survival after treatment with cyclosporine. III. Further characterization of the CD4+ suppressor cell and its mechanisms of action.

The cellular basis of the specific unresponsiveness that develops in DA rats treated with cyclosporine (CSA) for 10 d after grafting a PVG heart was examined using an adoptive transfer assay. CD4+ cells from rats with long survival grafts specifically lack the capacity to restore PVG heart graft rejection, and can also inhibit the capacity of naive T cells to restore rejection, while in the first few weeks post-transplant, both CD4+ and CD8+ T cells from CSA-treated hosts have the capacity to effect PVG graft rejection. In this study, we demonstrated the CD4+ suppressor cells also had the capacity to inhibit restoration of rejection by CD4+ cells from CSA-treated DA rats recently transplanted with PVG hearts, and from rats sensitized to third party, but not from those specifically sensitized to PVG. They also inhibited the capacity of both naive CD8+ and sensitized CD8+ cells to effect rejection. These results showed that the CD4+ suppressor cell was capable of overriding the capacity to effect rejection of the CD4+ cell and activated CD8+ cells that were present in the CSA-treated host shortly after transplantation. The failure of naive CD8+ cells to augment suppression and the capacity of CD4+ suppressor cells to transfer unresponsiveness to irradiated hosts in which regeneration of CD8+ cells was abolished by thymectomy suggested that it was the CD4+ cell alone that mediated suppression. However, the failure of CD4+ suppressor cells to reinduce unresponsiveness in irradiated hosts whose CD8+ cells had been depleted by therapy with the mAb MRC Ox8 showed that a radioresistant CD8+ cell was required to reestablish the state of specific unresponsiveness. The induction of CD4+ suppressor cells in thymectomized hosts suggested that these cells were derived from long-lived CD4+ lymphocytes. However, their sensitivity to cyclophosphamide and their loss of suppressor function both after removal of the graft and after 3 d in culture demonstrated that the suppressor cell itself had a short lifespan. The CD4+ suppressor was shown to be MRC Ox22+ (CD45R+), MRC Ox17+ (MHC class II), and MRC Ox39+ (CD25, IL-2-R). These studies demonstrated the CD4+ suppressive cell identified in rats with specific unresponsiveness induced by CSA therapy had many features of the suppressor inducer cell identified in in vitro studies of the alloimmune response.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

A quantitative analysis of T lymphocyte populations in human liver allografts undergoing rejection: the use of monoclonal antibodies and double immunolabeling.

The aim of this study was to quantitate T-cell populations infiltrating portal tracts, bile ducts and hepatic lobules in 82 biopsy specimens from 25 patients after orthotopic liver transplantation. Biopsy specimens taken immediately after revascularization of the graft were used as controls. Patients studied include 18 with initial rejection episodes, 11 with unresolved rejection, five with vanishing bile duct syndrome and eight patients with other forms of liver injury. Quantitation was done in a blinded fashion for the first 20 biopsy specimens. A double immunolabeling technique was used to simultaneously immunolabel bile duct structures (with anti-major histocompatibility complex class II or antikeratins) and lymphoid populations (with anti-CD2, anti-CD4 or anti-CD8). This facilitated the accurate quantitation of intraepithelial lymphocytes within bile ducts. This technique also enabled simultaneous detection of CD4 and CD8 antigens on lymphocytes in portal tracts. The predominant lymphocyte subtype within biliary epithelium during acute and chronic rejection was of the CD2+/CD8+ phenotype. CD8+/CD4+ ratio in bile ducts was approximately 5:1 in acute, unresolved and chronic rejection. In vanishing bile duct syndrome, double immunolabeling enabled the detection of destroyed interlobular bile duct remnants that were not apparent on routine hematoxylin and eosin staining. Attached to some of these structures were CD8+ lymphocytes. Lobular CD8+ cells were not prominent in acute rejection but increased significantly in biopsy specimens from patients with unresolved and chronic rejection. In chronic rejection, a selective increase was seen in these CD8+ cells in centrizonal regions.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Monoclonal↗
PubMed1990

Evaluation of subclinical depression in children using self-, peer-, and teacher-report measures.

This study reports on several classification issues utilizing the Children's Depression Inventory (CDI), the Child Behavior Checklist-Teacher Form (CBCL-T), and the Peer Nomination Inventory of Depression (PNID). The first sample contained 752 public school children in grades 5, 6, and 9. A second sample of 142 fifth-graders was included to have an additional PNID comparison group. Results revealed moderate correlations between the CDI and the CBCL-T and PNID. Use of multiple criteria for selecting children as depressed was discussed, and selection rates using multiple measures with either strict or lenient cutoff scores were given. Normative data on the PNID were evaluated, and it was suggested that norms for the PNID may not be generalizable to other samples. Finally, race and gender analyses showed that CDI scores for females were significantly higher than for males, whereas CDI scores for Hispanics were significantly higher than for non-Hispanic whites. However, Omega-squared analyses for these two variables showed this to be of little practical significance.

Adolescent↗
PubMed1990

Specific unresponsiveness in rats with prolonged cardiac allograft survival after treatment with cyclosporine. IV. Examination of T cell subsets in graft-versus-host assays.

In DA rats grafted with PVG hearts a short course of cyclosporine induces a state of specific unresponsiveness. In animals with grafts surviving greater than 75 days, the W3/25+ (CD4+) subset loses its capacity to mediate rejection of PVG but not third-party heart grafts when transferred into irradiated DA hosts. In this study we examined whether there was an associated change in the capacity of peripheral lymphoid T cell subsets from unresponsive animals to induce graft versus host (GVH) reactivity. First we demonstrated that there is synergy between naive CD4+ and CD8+ cells in the popliteal lymph node PLN assay, but that alone, only CD4+ and not CD8+ cells proliferate. Unfractionated and CD4+ cells from unresponsive animals produced similar PLN enlargement in both donor-specific (DAxPVG)F1 hosts and third-party (W/FxDA)F1 hosts. This enlargement was comparable to that produced cells from naive and specifically sensitized hosts. MRC OX8+ cells from both unresponsive and naive hosts did not produce PLN enlargement unless large numbers were injected; small numbers of sensitized MRC OX8+ cells produced specific PLN enlargement CD4+ cells from CsA-treated DA did not respond to DA anti-PVG idiotype in an in vivo assay adapted from the host versus graft (HVG) PLN assay. As the PLN assay does not test cells capacity to effect tissue damage, cells from CsA-treated DA rats were tested in a lethal GVHD assay. These cells had the same capacity to induce lethal GVH in irradiated (DAxPVG)F1 and (DAxW/F)F1 hosts. The normal response of cells from unresponsive animals in both proliferative and effector GVH assays shows that cells with the potential to respond to PVG alloantigen and mediate tissue damage are present in unresponsive animals but are prevented from mediating rejection, possibly due to the relatively weak immune stimulus of an organ graft.

Animals↗
PubMed1990

Current status of renal transplantation.

The success rate of renal transplantation has improved considerably during the past decade, with substantial improvements in both graft and patient survival. The quality of graft function, however, and not graft survival alone is increasingly determining the standards by which transplantation outcome is being judged. As the demand for kidney transplants continues to rise and transplants are being offered to an ever-increasing number of patients, organs are being sought from new supply pools and efforts are being made to use current resources more efficiently. Improvements in clinical management have allowed short-term complications such as infection and rejection to be better prevented or better diagnosed and treated. Fundamental advances in the understanding of the immunologic processes underlying both allograft rejection and acceptance and the introduction of new immunosuppressive agents have allowed a better use of drug therapy and have moved the goal of acquired transplant tolerance closer to attainment. With improved initial transplant success rates, the long-term transplantation outcome is becoming more important. The role of tissue matching in preventing chronic rejection is becoming more appreciated, and the long-term risks of malignancy, arteriosclerosis, and chronic rejection are being better recognized and managed.

Graft Rejection↗
PubMed1989

Cellular basis of allograft rejection in vivo. V. Examination of the mechanisms responsible for the differing efficacy of monoclonal antibody to CD4+ T cell subsets in low- and high-responder rat strains.

MRC OX35, an anti-CD4 mAb, was used to treat high responder Wistar Furth (W/F) (RT1u) and low responder DA (RT1a) rats which had been grafted with directly vascularized hearts from PVG (RT1c) rats across a full MHC plus non-MHC incompatibility. Four doses of mAb at 7 mg/kg given in the first 2 wk postgrafting induced indefinite graft survival (greater than 150 days) in DA hosts, but only delayed rejection to 18 to 42 days in W/F as compared to rejection times of 6 to 8 days in untreated rats. The extension of MRC OX35 treatment to 6 wk in W/F rats induced indefinite graft survival in three of six rats. During treatment MRC OX35 therapy only partially depleted CD4+ cells, and all circulating CD4+ cells were coated with MRC OX35. The capacity of naive CD4+ and CD8+ cells from W/F and DA to be activated to PVG alloantigen was compared both in vitro in an MLC assay and in vivo by an adoptive transfer assay of their capacity to restore rejection of PVG heart grafts in irradiated syngeneic hosts. CD4+ cells from both W/F and DA proliferated in MLC and restored graft rejection. W/F CD8+ cells both proliferated in MLC and restored rejection, but DA CD8+ cells neither proliferated nor reconstituted rejection. Examination of lymphocytes from MRC OX35 treated hosts with long-surviving grafts showed that they were neither depleted of CD4+ T cells nor did they lack the capacity to proliferate to PVG Ag in MLC, this response being similar to that to third-party Ag or by naive lymphocytes. Compared to first-set rejection, PVG skin graft rejection was delayed 2 to 3 days in W/F and 10 to 12 days in DA rats with long-surviving grafts after MRC OX35 therapy, whereas they rejected third-party skin grafts in first-set tempo. These studies show that differences in graft survival in anti-CD4 treated low and high responder strains may be due to the inherent capacity of CD8+ cells to be activated to effect rejection independent of CD4+ cells in W/F but not in DA. In those hosts that accept grafts, there is no evidence of clonal deletion, but there appears to be a form of unresponsiveness akin to that induced in adult rats by other immunosuppressive therapies that protects the graft from rejection.

Animals↗
PubMed1989

Mechanisms maintaining antibody-induced enhancement of allografts. II. Mediation of specific suppression by short lived CD4+ T cells.

In DA rats grafted with PVG hearts, the injection of 1 ml of Wistar-Furth x DA)F1 anti-PVG serum on the day of grafting prevents rejection and induces a state of specific unresponsiveness. An adoptive transfer assay was used to test the capacity of T cell subsets, taken from rats given enhancing serum, to either restore rejection or to transfer unresponsiveness to syngeneic hosts irradiated with 9 Gy and grafted with donor (PVG) or third party (Wistar-Furth) hearts. W3/25+ (CD4+) cells from these animals retained some capacity to restore rejection until 50 days posttransplant, after which they invariably failed to restore PVG graft rejection but retained the capacity to effect Wistar-Furth rejection. At this time CD4+ cells were also capable of inhibiting naive but not specifically sensitized CD4+ cells capacity to restore PVG graft rejection in irradiated hosts. The development of CD4+ suppressor cells was concurrent with the appearance of clinically evident unresponsiveness in the host. MRC Ox8+ (CD8+) cells from enhanced rats when mixed with naive CD4+ cells delayed rejection in adoptive recipients but did not reestablish unresponsiveness. Paradoxically, the CD4+ cells that transfer unresponsiveness to the adoptive host proliferate such as normal cells in MLC to both donor and third party alloantigen. Unfractionated cells, CD4+ or CD8+ cells did not proliferate to relevant idiotype in vitro. The CD4+ cells after 3 days in culture, with either alloantigen or idiotype-bearing stimulator cells, lost their capacity to suppress in the adoptive transfer assay. The maintenance of specific unresponsiveness was thus shown to be due to a CD4+ suppressor T cell whose function was lost in culture, and therefore could not be detected in MLC or idiotype assays.

Adjuvants, Immunologic↗
PubMed1989

T cell subsets mediating lethal graft versus host disease: demonstration that synergy between CD4+ and CD8+ T cells is the predominant mechanism in low responder rat strains.

T cell subsets from rat strains that have been characterized as high and low responders to alloantigen were examined for their capacity to mediate lethal graft versus host disease (GVHD) across strain combinations incompatible for class I, class II, and non-MHC antigens. Inocula of 5 X 10(7) lymph node and spleen cells (LC) from low responder DA (RT1a) and high responder W/F (RT1u) strains caused lethal GVHD in (W/F X DA)F1 hybrids given 6 Gy whole body irradiation. W/F CD4+ (W3/25+) cells (2 X 10(7], equal to the number in 5 X 10(7) LC mediated lethal GVHD but 10(8) DA CD4+ cells were required to cause lethal GVHD. CD8+ (MRC OX8+) cells (5 X 10(7] from W/F rats alone caused lethal GVHD but those from DA rats could not. Mixtures of CD4+ and CD8+ DA T cells, equivalent to the number in 5 X 10(7) LC, did mediate lethal GVHD, demonstrating that synergy between the subsets was the predominant mechanism with DA cells. These results suggest that differences in alloreactivity between the strains tested may be due to alternate requirements for the alloactivation of T cell subsets; the high responder subsets being self-sufficient and the low responder subsets being dependent upon each other.

Animals↗
PubMed1989

Expression of leucocyte and lymphocyte adhesion molecules in the human kidney.

Leucocyte interaction with other cells is facilitated by the adhesion molecules, leucocyte function-associated antigen-1 (LFA-1)-binding to intercellular adhesion molecule-1 (ICAM-1) and for T cells and natural killer (NK) cells the binding of LFA-2 (CD2) to LFA-3. As these interactions are critical for the mediation of graft destruction by effector T cells, we examined whether there was a change in the expression of these molecules during rejection compared to normal kidneys. In normal kidneys, peritubular and glomerular capillaries and large vessel endothelium expressed ICAM-1 and LFA-3, but tubular cells expressed only low levels of LFA-3. LFA-1-expressing cells, which were probably macrophages, were observed in the glomerulus. A few scattered LFA-1-expressing cells in the interstitium were probably tissue macrophages or dendritic cells, and only occasional interstitial mononuclear cells expressed LFA-2. During rejection, there was an infiltrate of mononuclear cells expressing LFA-1 and the T cell and NK cell component of the infiltrate expressed LFA-2. Neither of these markers was expressed by kidney parenchymal cells except for one allograft with severe rejection which showed LFA-1 beta chain expression by some tubular cells. Tubular cells had increased expression of ICAM-1 during rejection but there was no increase in LFA-3. The importance of LFA-2 and ICAM-1 expression on kidney tubular cells for adhesion of activated T cells was also examined in an in vitro system.(ABSTRACT TRUNCATED AT 250 WORDS)

Antigens, CD↗
PubMed1989

Specific unresponsiveness in rats with prolonged cardiac allograft survival after treatment with cyclosporine. II. Sequential changes in alloreactivity of T cell subsets.

A 10-day course of cyclosporine treatment inhibits the capacity of DA rats to reject PVG heart grafts and leads to the development of specific unresponsiveness and indefinite graft survival, which is mediated by a W3/25+ (CD4+) suppressor cell. In this study the sequential changes in the alloreactivity of the CD4+ and CD8+ subsets of CsA-treated DA rats were examined. During the induction phase, 8 and 20 days posttransplant, W3/25+ cells retained normal alloreactivity in that they adoptively restored PVG heart graft rejection in irradiated DA rats. By day 50 they had lost their capacity to restore rejection of PVG grafts but still retained their capacity to effect third party W/F graft rejection. W3/25+ cells from control grafted rats adoptively restored PVG graft rejection even at 75 days posttransplant, suggesting that the loss of alloreactivity of W3/25+ cells in CsA-treated rats was due to the prevention of rejection by CsA, and not a consequence of sensitization to alloantigen. MRCOX8+ cells from CsA-treated rats showed some evidence of sensitization at days 8 and 20 but lost this by day 50. These studies showed that during the induction phase, normal alloreactivity of W3/25+ cells is retained and sensitization of MRCOX8+ cells occurs. Specific loss of reactivity and suppressor potential of W3/25+ cells developed later, when specific unresponsiveness to second donor strain grafts developed in these hosts.

Animals↗
PubMed1989

Microvascular destruction in renal transplant rejection.

In normal kidneys, peritubular and glomerular capillaries can be readily identified by their intense expression of HLA class I and class II compared to other cells within the graft. This high density of expression of MHC, plus their exposure to activated circulating lymphocytes, makes these cells the likely early and primary target of rejection responses. The fate of these capillaries during renal allograft rejection was examined using an indirect immunoperoxidase staining technique and monoclonal antibodies to class I and class II MHC antigens as well as other antigens on capillary endothelium including ICAM-1, LFA-3, and a novel antigen identified by E1.5. Expression of HLA-DR by peritubular capillaries was decreased during rejection, and this disappearance of peritubular capillaries with severe rejection was confirmed by loss of other markers of microvascular endothelium. These studies suggest peritubular capillaries may be the major target of the acute rejection response, and the techniques described allow assessment of degree of damage to these structures in renal allograft biopsies.

Antibodies, Monoclonal↗
PubMed1989

Therapy with monoclonal antibodies to CD4: potential not appreciated?

The assumption that CD8+-cytotoxic cells effect graft rejection has diverted many in clinical and experimental transplantation into ignoring the tremendous potential of anti-CD4 monoclonal antibodies as immunosuppressive therapy. Experimental studies over the past several years has shown that anti-CD4 monoclonal antibodies have effects on prolonging graft survival equal to or greater than those of cyclosporine. This therapy has the unique capacity to induce tolerance to the monoclonal antibody itself, thus preventing the production both of antiidiotypic and antimouse immunoglobulin antibodies. Further, many animals develop tolerance to other antigens, including grafted tissue, raising the potential of eliminating the need for long-term immunosuppression. Synergy between anti-CD4 monoclonal antibodies and other immunosuppressives, including anti-CD8 antibodies and cyclosporine, has also been demonstrated. Continued investigation to determine the best monoclonal antibody to use in humans with respect to its epitope, immunoglobulin subclass, and capacity to deplete CD4+ cells is required to maximize the potential of this therapy before clinical trial.

Animals↗