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Biomedical subjects

N R Sinclair

Publications and source records attributed to N R Sinclair.

At least 19 recordsLinked to original sources
PubMed1992

Low-dose steroid therapy in cyclosporine-treated renal transplant recipients with well-functioning grafts. The Canadian Multicentre Transplant Study Group.

OBJECTIVE: Low-dose prednisone given on alternate days as a steroid adjunct to cyclosporine therapy was investigated primarily for its influence on kidney graft and patient survival and, secondarily, on renal function and complications. DESIGN: Multicentre randomized double-blind clinical trial. SETTING: Fourteen Canadian transplant centres. PATIENTS: A total of 523 patients with well-functioning renal transplants (cadaveric grafts or grafts from living related donors) and without active graft rejection reactions who were entered into the trial from 1982 to 1985. INTERVENTION: Patients were randomly assigned 90 days after transplantation to receive either placebo (260 patients) or low-dose prednisone (263 patients). MAIN OUTCOME MEASURES: Graft and patient survival. MAIN RESULTS: After at least 5 years of follow-up 50 patients assigned placebo had lost their graft and 17 had died; the corresponding figures for those assigned prednisone were 38 and 16. After an average interval of 1.4 years 143 patients in the placebo group and 123 patients in the prednisone group had stopped therapy with the test drug or had had their treatment group decoded or both. Patients were withdrawn from the study 2 years after stopping the test therapy. The actuarial 5-year graft survival rates were 73% and 85% in the placebo and prednisone groups respectively (p = 0.03), and the actuarial 5-year patient survival rates were 92% and 94% respectively (p = 0.6). This analysis included 43 and 29 graft losses and 14 and 12 deaths in the placebo and prednisone groups respectively. Weibull parametric modelling of graft survival identified the following variables as risk factors for graft loss: histocompatibility leukocyte antigen B (HLA-B) mismatching (p = 0.007), donor death from cerebrovascular accident (p = 0.01), increased donor age (p = 0.02) and being a male recipient (p = 0.05). When these factors were included in the Cox proportional hazards model, the influence of assigned treatment on graft survival was reduced to p = 0.1. Donor death from cerebrovascular accident (p = 0.002), diabetes mellitus in the recipient (p = 0.02) and increased recipient age (p = 0.05) were risk factors for patient death. Renal function and incidence of complications were similar in the treatment groups. CONCLUSIONS: Continued administration of low-dose prednisone on alternate days is advisable, particularly in patients with cadaveric grafts and those with previously failed transplants.

Adult↗
PubMed1992

Regulation of an anti-self response: lack of influence of exogenous DNA on the in vitro anti-DNA response.

Anti-DNA antibodies occur in outwardly normal individuals as well as in various forms of autoimmune disease. A number of publications have reported on the ability of added DNA to either induce or inhibit the in vitro production of anti-DNA antibody. In this study, the in vitro production of IgM anti-single stranded DNA (alpha ssDNA) antibody by spleen cells from normal or autoimmune mice neither depends upon, nor is inhibited by, the addition of high molecular weight DNA to the culture. The decrease in antibody forming cell plaques, reported previously, is due solely to the artifactual carryover of inhibitory material into the assay system, where it interferes with the expression of plaques by preventing anti-DNA antibody from reaching the DNA-coated erythrocytes. Similarly, plaque forming cell (PFC) methods have not detected alpha ssDNA antibody producing cells in murine spleen cells without culturing, but various other systems for measuring antibody normally detect anti-DNA antibodies in vivo. This discrepancy is also due to inadequate washing of freshly harvested cells to rid them of inhibitory substances which prevent them from registering as PFC. While S1 nuclease was able to prevent PFC interference by purified DNA, it did not remove the inhibitory substances from the culture supernatants; therefore substances other than ssDNA are able to interfere with alpha ssDNA PFC, suggesting that the alpha ssDNA PFC detected are polyspecific. Levels of alpha ssDNA PFC in spleen cells from non-autoimmune mice begin at one-quarter of the peak in vitro response, decrease to one-tenth in the first day and then reach peak values after 3 to 5 days of culture, suggesting that spleen cells are actively producing alpha ssDNA antibodies an in vivo and that then in vitro response is observed. Despite this evidence for an in vitro alpha ssDNA response, this response was not inhibited markedly by 1000 rad gamma-irradiation, while the response to sheep erythrocytes (SRBC) was profoundly suppressed. These findings suggest that anti-self B lymphocytes are resistant to interphase, possibly apoptotic, lymphocyte death due to gamma-irradiation, while anti-nonself B lymphocytes remain sensitive.

Animals↗
PubMed1990

How many signals are enough?

The many signals that control the progress of various immune responses to both foreign and self antigens can be divided into no less than three major groups. The first group is the initial positive stimulus, associated with activation events through antigen receptors and their associated proteins. These signals launch lymphocytes in their response to antigen, either foreign or self. The second group of signals is negative and involves various end products and interactions between cells, all recognizing antigen. These signals are endogenous to the reacting cell, or nearly so (two interacting cells from the same clone, daughter cells, which are in the same locale and bind to the same ligand). The third group (the prevention of end product feedback, involving various forms of antigen presentation, T cell contributions, rheumatoid factor activity, and other mechanisms) is more likely to occur with nonself antigens, which are temporally and spatially more restricted than self antigens. Experimental evidence for this immunological schema is summarized and clarified in its relationship to the Bretscher-Cohn theory of self-nonself recognition and to suppressor cell and idiotype-antiidiotypic theories.

Animals↗
PubMed1990

Lack of high avidity IgM anti-ssDNA antibodies in cells from autoimmune-prone and autoimmune mice.

Non-autoimmune prone CBA mice were compared with autoimmune prone NZB, NZW, and (NZB x NZW)F1 mice for the ability of their splenic cells to produce anti-ssDNA-forming cells spontaneously in vitro, measured in the plaque forming cell assay. The number of antibody forming cells was measured and the relative avidity of antibody produced determined using a plaque inhibition assay. Splenic lymphocytes from young animals of a non-autoimmune strain (CBA/J) were shown to be capable of generating anti-ssDNA IgM antibody-forming cells in culture which displayed a higher avidity for antigen than that from autoimmune-prone or frankly autoimmune mice. Since an increased switching from IgM to IgG autoantibody production and defects in Fc-mediated signalling by IgG antibody have been identified in autoimmunity, we suggest that the metabolic block, normally in force in non-autoimmune-prone animals, accounts for this elevated avidity of IgM autoantibody.

Aging↗
PubMed1990

Clonalism--the myth?

Two regulatory mechanisms, based on the contrasting concepts of imprinting (clonal theories and idiotypic networks) and of ongoing regulation of immune responses (by antigen and end products with specificity for antigen), give rise to different predictions and approaches to the question of autoimmunity and autoimmune disease. Both concepts have legitimacy, however, if a ranking in terms of explicative power must be given, ongoing regulation is more plausible since it accounts more fully for basic events in immune responses and in autoimmune phenomena. Many instructive findings have emerged from experiments based on this latter concept, furthermore, the approach has only received limited notice and, thus, has not yet been exhausted.

Animals↗
PubMed1989

Rheumatoid factor blocks regulatory Fc signals.

Immunosuppressed cultures of murine spleen cells, partly deprived of T cells and antigen-stimulated, can be reconstituted to near full activity in their antibody-forming cell response with murine rheumatoid factors (RF). The dose of RF required for recovery of 50% of the reconstitutable immune response was 10-100 ng and reconstitution was blocked by intact murine IgG added to the cultures. IgG subclass specificity of RF was demonstrated; RF specific for IgG2a was more potent than RF specific for IgG1 in reconstituting the response. Synergy was observed between RF added at culture initiation and late-acting B-cell differentiation factors. The greater the degree of T-cell deprivation, the more stringent the conditions needed for reconstitution. Suitable conditions for reconstitution with profound T-cell depletion included the limited reconstitution by specific RF, the synergistic action of RF with late-acting T-cell-replacing supernatants, and multiple additions of a number of RFs to the cultures on Days 0, 1, and 2. RF was also shown to block Fc-dependent immunosuppression by added antigen-antibody complexes. These results are interpreted as favoring the hypothesis put forward previously that the normal production of RF acts to reduce T-cell dependency by preventing negative Fc signal transmission by immune complexes on the B-cell surface. Abnormal production of RF may be a primary destabilizer of the immune responses leading to autoimmunity.

Animals↗
PubMed1989

Rheumatoid factor and Fc signaling: a tale of two Cinderellas.

Signaling to lymphocytes depends not only upon the interaction of receptors with specific antigen, but also upon antigen nonspecific receptors which receive input from two classes of molecules, immunologically specific end products and lymphokines. These represent the central elements in the physiologic stimulation of immune responses to both self and foreign antigens. This review is dedicated primarily to describing the function of physiologically active receptors for end product which are central to end product feedback in normal immune responses. The emergence of autoimmunity as a pathologic process resultant from a defective end product signaling mechanism is described.

Animals↗
PubMed1987

Interference with Fc signals increases an antibody response by T-cell-deprived cultures to a T-dependent antigen.

Affinity column purified goat anti-mouse immunoglobulin antibodies specific for the Fc portion of IgG increased an in vitro antibody response to a T-dependent antigen when T cells were limiting. Picogram amounts of specific anti-Fc antibody at culture initiation and nanogram quantities up to 3 days were required to demonstrate this effect. The demonstration of reconstitution by anti-Fc antibodies requires that the cultures be T-cell depleted and stimulated by antigen. These results support the concept that anti-Fc antibody and T cells block endogenously generated negative Fc signals.

Animals↗
PubMed1986

Immune response after gastric bypass and weight loss.

The immune response of 22 morbidly obese patients was measured before and 6 months after gastric bypass. In-vivo skin testing was carried out using five recall antigens. In-vitro response assessed the ability of isolated lymphocytes to take up radioactive thymidine after culture with the same antigens. The mean (+/- SD) preoperative weight of the patients of 122 +/- 14 kg declined by 33.5 +/- 8 kg after 6 months. The number of positive skin tests increased from a mean (+/- SEM) of 1.8 +/- 0.17 to 2.1 +/- 0.17 (p = 0.2). Mean (+/- SEM) induration of the skin-test response assessed at 24 hours after antigen injection increased from 4.7 +/- 0.6 mm to 5.5 +/- 0.6 mm (p = 0.35) and at 48 hours from 5.4 +/- 0.7 mm to 6.9 +/- 0.9 mm (p = 0.05). One patient who was anergic before gastroplasty responded normally 6 months later after substantial weight loss. In-vitro response, expressed as a stimulation index (+/- SEM), increased from 4.71 +/- 0.65 to 7.95 +/- 1.56 (p = 0.06) for the average of all antigens and from 12.85 +/- 2.05 to 15.79 +/- 2.84 (p = 0.2) for the largest response. The authors conclude that the response to test antigens in vitro and in vivo is not reduced significantly 6 months after gastric bypass and profound weight loss. Patients with severe vomiting, rapid weight loss or sepsis may respond differently and require individual assessment.

Adult↗