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Biomedical subjects

R M Ferguson

Publications and source records attributed to R M Ferguson.

At least 127 records · Page 7Linked to original sources
PubMed1989

In vivo mechanisms of alloreactivity. VI. Evidence that alloantigen deposition initiates both local and systemic mechanisms that influence CTL accumulation at a graft site.

We have used sponge matrix allografts to investigate how alloantigen influences the pattern of CTL accumulation at a graft site. These studies employed two limiting dilution analysis techniques to monitor CTL accumulation. One technique quantitates the subpopulation of CTL that show evidence of in vivo contact with graft alloantigens (alloantigen-conditioned CTL or cCTL). The other quantitates all CTL with specificity for graft alloantigens, regardless of their differentiative status. Using these techniques, we have demonstrated that sponge allografts acquire three types of CTL: (a) donor-reactive CTL precursors (pCTL), (b) donor-reactive cCTL, and (c) pCTL with irrelevant antigen specificity. Sponge isografts rarely acquire LDA-detectable CTL, unless they receive a concurrent allogeneic stimulus at a distant anatomic site. In that instance, sponge isografts acquired pCTL, but not cCTL. This indicates that an ongoing immune response to alloantigens can influence the immunologic characteristics of an unrelated inflammatory response occurring elsewhere. We further observed that sponge isografts can be made to acquire alloreactive cCTL only when specific alloantigens are placed in the isograft. This indicates that specific grant alloantigen present at the graft site plays a necessary but undefined role in the acquisition or development of cCTL in sponge allografts. Collectively, these data demonstrate that alloantigen deposition initiates both local and systemic mechanisms that influence alloreactive CTL accumulation at a graft site.

Animals↗
PubMed1988

Maternal age and incidence of low birth weight at term: a population study.

A total of 184,567 singleton live births with gestational ages of 40 weeks were examined from the 1980-1984 Illinois birth certificate data to determine the independent effect of maternal age on the incidence of low birth weight at term. The incidence is highest in mothers less than 17 years of age (3.2%) and gradually declines with advancing maternal age to reach 1.3% in women aged 25 to 34 years. It increases to 1.7% for those greater than 35 years of age. To separate out the independent effect of maternal age on the incidence of low birth weight infants at term, the presence of other maternal factors, such as race, education, parity, marital status, and prenatal care, were adjusted by use of a series of multiple logistic regression analyses. All of these analyses consistently demonstrated that the adjusted risk for low birth weight at term is the lowest in teenagers and increases with advancing maternal age. These results indicate that the high incidence of this factor in young mothers apparently reflects their poor sociodemographic and prenatal care status. Advancing maternal age is associated with a decreased potential for fetal growth, possibly reflecting biologic aging of maternal tissues and systems or the cumulative effects of disease.

Adolescent↗
PubMed1988

In vivo mechanisms of alloreactivity--IV. Cyclosporine differentially impairs accumulation of donor-reactive CTL but not donor-reactive alloantibody in murine sponge matrix allografts.

We have studied the influence of Cyclosporine on accumulation of donor-reactive CTL, donor-reactive cytotoxic alloantibody and as an immunosuppressive drug in individual murine sponge matrix allografts. During these studies, we observed that: (1) levels of CsA in sponge matrix allografts rapidly reach levels that are immunosuppressive in vitro, i.e. greater than 100 ng/ml, following daily i.m. or subsponge CsA injections of 30 mg/kg; (2) donor-reactive CTL continue to accumulate and develop cytolytic activity in sponge allografts from mice treated i.m., but not subsponge with CsA; (3) delay or interruption of subsponge CsA therapy decreases the ability of CsA to block CTL accumulation in sponge matrix allografts; (4) relatively high local concentrations of CsA appeared to be necessary to influence CTL behavior in sponge matrix allografts; (5) CsA therapy had a different effect on the development of donor-reactive cytotoxic alloantibody. Intramuscular CsA therapy potentiated alloantibody production whereas subsponge CsA therapy temporarily delayed alloantibody production. These studies demonstrate that CsA can differentially impair the accumulation of donor-reactive CTL, but not donor-reactive alloantibody in sponge matrix allografts. These results have several theoretical and clinical implications. They also illustrate the utility of sponge matrix allografts from concomitant in vivo immunologic and pharmacologic studies at the site of a localized immune response.

Animals↗
PubMed1988

Cyclosporine nephrotoxicity in spontaneously hypertensive rats.

In the present study, we investigated the combined, nephrotoxic effects of cyclosporine (CsA) and hypertension in young, spontaneously hypertensive rats (SHR). After 4 weeks of CsA therapy, SHR, compared with oil-treated SHR, showed an acceleration in the development of hypertension, mild renal insufficiency, and the accumulation of periodic-acid-Schiff-positive (PAS [+]) material in periglomerular arterioles. By electron microscopy, PAS(+) material was composed of intracytoplasmic inclusion bodies consistent with the accumulation of renin granules. This finding was demonstrated in SHR after 4 weeks of CsA therapy but not after 8 weeks of therapy. By contrast, CsA had no significant effect on blood pressure in Wistar-Kyoto rats, a normo-tensive control. To investigate the effect of unilateral nephrectomy (UNx) on the development of renal histopathologic changes in this model, SHR were subjected to uninephrectomy and CsA or oil therapy. UNx accelerated the development of hypertension in all SHR groups. SHR subjected to UNx demonstrated no renal histopathologic changes after CsA or oil treatment. In conclusion, CsA accelerates the development of hypertension in SHR, and this effect is probably renin-mediated. The combination of UNx and CsA therapy in the SHR does not result in significant renal histologic damage.

Animals↗
PubMed1988

Improved immediate function of renal allografts with Belzer perfusate.

The characteristics of 254 cadaveric kidneys were evaluated and the incidence of immediate function identified. The Belzer perfusate was used primarily (n = 140) and secondarily (n = 14) in combination with pulsatile machine perfusion. These two groups were compared with a previous group of kidneys machine-perfused with silica gel (cryoprecipitated human plasma). The incidence of immediate function of the group primarily perfused with Belzer perfusate was statistically significantly improved over that of the silica gel. The secondarily perfused Belzer group, "imported" kidneys previously preserved with simple cold storage, had notably longer periods of preservation and higher resistances on the machine. However, 100% of this group functioned immediately. Other findings in this study show that the Belzer perfusate allows for improved parenchymal function posttransplant, as noted by a more rapid clearance of serum creatinine posttransplant. When comparing the immediate function group with those suffering early dysfunction, there is a statistically significant increased resistance on the machine in the latter group. This allows for prediction of immediate function based on perfusion characteristics of the kidney. The Belzer perfusate, composed of metabolic substrates for high-energy phosphate production, improves the incidence of immediate function in machine-perfused kidneys, as well as improved qualitative function posttransplant. It also is effective as a "rescue" mechanism in previously simple cold-stored (ATP-depleted) kidneys.

Adenosine Triphosphate↗
PubMed1988

Histamine type-2 receptor antagonist immune modulation. I. Increased cell-mediated cytotoxicity in normal and in down-regulated systems.

Cimetidine, a histamine type-2 receptor antagonist, is capable of immunoregulating T cell-mediated proliferative responses in both man and mouse. We present data that show that cell-mediated cytotoxicity (CMC) is also increased by cimetidine in normal and down-regulated murine splenocytes. Timed addition and removal of cimetidine from CMC generation cultures localizes the cimetidine effect to the first 24 hours of the alloantigen sensitization process. Cimetidine partially reverses CMC suppression by suppressor cells generated in vitro in a dose response manner; the result depends on the number of suppressor cells added. Mixed tumor lymphocyte cytotoxicity of splenocytes from syngeneic-tumor-bearing mice is increased by in vivo cimetidine treatment, which results in prolongation of concomitant tumor immunity. These data support the concept that cimetidine may have potential as a clinical immunofacilitator in down-regulated states of immunity.

Animals↗
PubMed1988

Frequency of human alloantigen-reactive T lymphocytes. III. Evidence that cyclosporine has an inhibitory effect on human CTL and CTL precursors, independent of CsA-mediated helper T cell dysfunction.

We have used limiting dilution analysis to study the behavior of alloantigen-reactive cytolytic T lymphocytes derived from human peripheral blood. During these studies, we found that the presence of cyclosporine in limiting dilution microcultures significantly impairs the subsequent development of alloantigen-reactive cytolytic T cell activity. As a result, CsA reduces the estimate of CTL precursor frequency by limiting dilution analysis. CTL frequency estimates are reduced by CsA in a dose-dependent manner, and concentrations of CsA that are readily achieved in human peripheral blood (100-1000 ng/ml) are capable of reducing estimates of CTL frequency by 90% to 100%. Further studies revealed that (1) human CTL derived either from fresh peripheral blood or from primary mixed lymphocyte cultures are sensitive to the suppressive effects of cyclosporine in limiting dilution microcultures, indicating that CsA influences both alloantigen-primed CTL and CTL precursors; (2) CsA impairs an immunologic event or events, that occurs for at least the first four days of limiting dilution microculture incubation; (3) CsA-mediated suppression is eliminated by separation of CTL from cyclosporine; (4) CsA blocks development of CTL generation, but not cell proliferation in limiting dilution microcultures; and (5) the CsA-mediated suppression is not reversed by supraoptimal concentrations of IL-2, high concentrations of gamma-IFN, or supplementation with the multiple lymphokines present in MLC supernatants. These data suggest that CsA may have a direct inhibitory influence on the differentiation of human CTL precursors that is independent of helper T cell dysfunction.

Cell Differentiation↗
PubMed1988

Serum cyclosporine kinetic profile. Failure to correlate with nephrotoxicity or rejection episodes following sequential immunotherapy for renal transplantation.

Cyclosporine (CsA) level monitoring in renal transplant recipients has been thought to aid in separating clinical episodes of nephrotoxicity from rejection. Twenty-four-hour CsA pharmacodynamic profiles were obtained from 85 consecutive primary renal transplant recipients in the immediate peritransplant period in order to determine the value of this test in predicting subsequent episodes of nephrotoxicity or rejection. All patients were treated with sequential antilymphoblast globulin/CsA following transplantation. Serum samples from each recipient were analyzed for CsA levels estimated by radioimmunoassay (RIA) four days after initiation of a daily single oral CsA dose (10 mg/kg/day). A total of 52 episodes of rejection and 303 episodes of nephrotoxicity occurring within the first six months posttransplant were correlated with selected parameters from the immediate posttransplant CsA kinetic profile. For each profile these parameters were maximum CsA level, time to maximum CsA level, minimum CsA level, 95% clearance time of CsA, and total CsA accumulation and clearance during the 24 hr following ingestion of CsA. No significant correlation was found between any of these parameters and either the incidence or frequency of rejection or nephrotoxic episodes, as determined by least-squares linear regression analysis. Furthermore, following a single oral dose of CsA (10 mg/kg/day), no correlation could be found between the dose and the absorption, accumulation, metabolism, and clearance of the drug. In conclusion, maximum CsA level, time to maximum CsA level, minimum CsA level, 95% clearance time of CsA, and total CsA accumulation and clearance measured from CsA kinetic profiles cannot be correlated with or predict the incidence of rejection or nephrotoxic episodes that subsequently occur during the first six months following renal transplantation.

Adolescent↗