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Biomedical subjects

M W Flye

Publications and source records attributed to M W Flye.

At least 145 records · Page 8Linked to original sources
PubMed1990

Kupffer cell blockade increases mortality during intra-abdominal sepsis despite improving systemic immunity.

The effect of Kupffer cell (KC) blockade on systemic immunity during intra-abdominal sepsis was evaluated. Gadolinium chloride, a rare earth metal, reduced KC phagocytosis by 75% when it was given to BALB/c mice for 2 days. Thereafter, control mice and mice with KC blockade underwent either a sham operation or a cecal ligation and puncture. As indicators of systemic cell-mediated immunity, delayed-type hypersensitivity responses to soluble antigen and cellular alloantigen were measured 24 hours after the abdominal operations. The activation of KCs was assessed by their in vitro interleukin 1 production. Control septic mice were profoundly immunosuppressed and demonstrated marked KC activation. Septic mice with KC blockade, however, demonstrated less systemic immune hyporesponsiveness and significantly reduced KC activation, but died more rapidly. We concluded that despite apparent improvement in systemic immunity by KC blockade during intra-abdominal sepsis, the resulting impairment in functional phagocytic integrity predisposes to significantly higher mortality.

Abdomen↗
PubMed1990

Kupffer cell blockade prevents induction of portal venous tolerance in rat cardiac allograft transplantation.

Pretransplant portal venous (pv) administration of donor antigen induces allospecific partial tolerance. Although the involved mechanism has not been defined, antigen presentation by Kupffer cells (KC) in the liver is considered to be critical. We evaluated the effect of KC blockade on this pv tolerance induction in Buffalo (RT1b) rats receiving Lewis (RT1(1] cardiac heterotopic allografts. Control rats received no treatment, while experimental animals received 25 X 10(6) ultraviolet B-irradiated (12,000 J/m2) donor spleen cells via either the iv (systemic intravenous) or the pv routes 7 days before transplantation. Gadolinium chloride (GdCl3), a rare earth metal known to inhibit KC phagocytosis, was given (7 mg/kg) 1 and 2 days before pv preimmunization. Cardiac graft prolongation was obtained by pv (MST = 13.3 +/- 1.9 days, n = 6, vs control = 7.3 +/- 0.5 days, n = 6; P less than 0.001) but not by iv preimmunization (7.7 +/- 0.7 days, n = 6, NS vs control). KC blockade abolished the pv tolerance, as indicated by abrogation of graft prolongation (PV + GdCl3 = 8.0 +/- 0.8 days, n = 6, NS vs control). These findings suggest that effective alloantigen uptake by KC in the liver is essential for the induction of pv tolerance in rat cardiac transplantation.

Animals↗
PubMed1990

Interleukin-6 production by endotoxin-stimulated Kupffer cells is regulated by prostaglandin E2.

Although its impact on the acute phase response is clear, little is known regarding the regulation of interleukin-6 (hepatocyte-stimulating factor) production. We evaluated its relationship with the potent immunosuppressive eicosanoid PGE2 in endotoxin (LPS)-stimulated Kupffer cells (KC). KC were harvested from collagenase-digested Wistar-Furth rat livers and purified (greater than 95% by phagocytosis) by adherence. Following overnight culture with or without the cyclooxygenase inhibitor indomethacin (10 microM), 5 X 10(5) KC were repleted with fresh media with or without 2.5 micrograms/ml LPS. Supernatant IL-6 levels (ng/ml) were measured with the B9.9 hybridoma proliferative bioassay, and PGE2 levels (ng/ml) by radioimmunoassay. Negligible supernatant IL-6 and PGE2 were measured at all culture intervals in unstimulated KC or those cultured with the LPS-inhibitor polymyxin-B (10 micrograms/ml). With LPS, KC IL-6 production increased in parallel with PGE2 for 24 hr before decreasing as PGE2 continued to rise. When indomethacin treatment blocked KC PGE2 production, IL-6 levels significantly increased. We conclude that PGE2 produced by activated Kupffer cells appears to down-regulate IL-6 secretion. Autocrine effects by PGE2 may locally regulate the hepatic acute phase response by limiting the KC-derived IL-6 available to act on neighboring hepatocytes.

Animals↗
PubMed1990

Comparison of culture and serology for the diagnosis of cytomegalovirus infection in kidney and liver transplant recipients.

This study compared culture, including the shell vial procedure, with serology, including IgM cytomegalovirus (CMV) antibody testing, for the diagnosis of CMV infection in 42 subjects undergoing cadaveric renal or liver transplantation. Of 35 subjects who developed active CMV infection, 31 had positive cultures, while IgM CMV antibodies were detected in 29. Subjects with symptomatic CMV infection were more likely than asymptomatic subjects to have positive cultures of leukocytes (17/18 vs. 9/17, P = .01). In contrast, symptomatic and asymptomatic subjects did not differ in their IgG or IgM CMV antibody test responses. In subjects with symptomatic infection, viral shedding typically began early in the course of infection, often preceding symptoms, while the serologic response usually followed the appearance of symptoms. With the use of the shell vial procedure to facilitate detection of positive cultures, symptomatic CMV infections following kidney or liver transplantation can be recognized earlier and more reliably using viral culture than by serologic testing.

Adult↗
PubMed1990

Augmentation of cell-mediated cytotoxicity following 50% partial hepatectomy.

The cytolytic responses of C3H/HeJ mice after 50% hepatectomy (PH) were assessed in a 4-hr 51Cr-release assay. Spleen cells (SC) (50 x 10(6] from normal or PH C3H/HeJ (H-2k) mice were sensitized with equal numbers of irradiated allogeneic DBA/2 (H-2d) spleen cells in a five-day mixed lymphocyte culture. Generated cytolytic activity was measured against 51Cr-labeled P815 mastocytoma (H-2d) and EL4 lymphoma (H-2b) target cells. The wet weight and cell numbers per spleen following 50% partial hepatectomy were 70% and 75% higher than the control values for the first 20 days, and then returned to normal levels by 21 days. The cytolysis by spleen cells from 2-, 14-, and 31-day PH mice were 89.3 +/- 0.7, 86.9 +/- 5.3, and 90.1 +/- 1.3%, respectively, compared with control (sham-operated) values of 56.0 +/- 1.0, 57.0 +/- 2.0, and 49.9 +/- 7.0% (P less than 0.03 at E/T 100:1). This enhanced cytolysis by PH spleen cells remained high for at least 118 days after the liver resection before returning to control levels by 268 days. Cytolytic effector cells in PH SC were generated at least 24 hr earlier than in control SC. When normal and PH cytolysis were compared following primary and secondary in vitro sensitization, the cytolytic levels of primarily-sensitized PH spleen cells were comparable to secondarily sensitized normal spleen cells. Furthermore, the primarily sensitized normal spleen cells did not show crossreactive cytolysis with EL4 target cells (H-2b), while both the primarily sensitized PH spleen cells and the secondarily sensitized normal spleen cells were significantly cross-reactive against the third party EL4 target cells. Adherent PH spleen cells appear to be responsible for this augmented cytolytic capacity since their coculture with normal nonadherent responder spleen cells increased control cytolysis by approximately 30%. These studied demonstrate that, following 50% partial hepatectomy, there is an immediate and sustained increase in the allospecific cytolytic response.

Animals↗
PubMed1990

The effects of early treatment of hereditary tyrosinemia type I in infancy by orthotopic liver transplantation.

Two infants with hereditary tyrosinemia secondary to fumarylacetoacetate hydrolase (FAH) deficiency underwent orthotopic liver transplantation at 14 and 16 weeks of age due to poor clinical and biochemical response to medical therapy. Prompt clearance of abnormal metabolites with improved mental alertness and appetite occurred with minimal perioperative complications. Both infants tolerated rapid institution of normal diets and have shown progressive growth and development in the first 36 months after transplantation. Early liver transplantation should be considered as an option for infants with certain inherited metabolic disorders with poor prognosis, such as tyrosinemia type I, who fail to respond to medical therapy.

Amino Acid Metabolism, Inborn Errors↗
PubMed1990

Reversible changes in tumor growth and metastatic behavior induced by immune pressure.

Prolonged exposure to host immunity was studied for its effect on several characteristics of a cloned 3-methylcholanthrene-induced fibrosarcoma. One million cells of a clone 10-O were injected subcutaneously into normal C3H/HeJ mice (clone 10-N) or tumor-immune mice (clone 10-I). After 10 passages in immune mice, 1 X 10(6) cells from 10-I tumor were transferred back into normal mice (clone 10-R). After 5 to 10 additional in vivo passages, clone 10-O, 10-N, 10-I, and 10-R tumors were transplanted into normal mice and observed for tumor growth rate, tumorigenicity, antigen specificity, metastatic potential, and plating efficiency. Clone 10-I after 10 passages in immunized mice grew significantly more slowly than did 10-O or 10-N clones, required more tumor cells to cause 50% tumor incidence in normal mice (tumorigenicity), and completely lost its capacity to metastasize spontaneously or experimentally. The plating efficiency in vitro of 10-I was also less than that of 10-O or 10-N. All these changes reversed after 5 to 10 passages of 10-I clone back into normal mice (10-R). Although immune pressure induced qualitative antigenic changes, as demonstrated by a tumor-rejection assay, and resulted in no cross-reactivity with control tumor clones (antigen specificity), the degree of immune response to its autologous clone in immune mice (immunogenicity) remained constant. These results suggest that several unrelated characteristics of this clone 10 can be phenotypically changed during the same period by immune pressure.

Amputation, Surgical↗
PubMed1990

Pretransplant portal venous administration of donor antigen and portal venous allograft drainage synergistically prolong rat cardiac allograft survival.

The effect of antigen given through the portal vein (PV) before transplantation or continuous drainage of a graft into the PV results in moderate prolongation of allograft survival. This study examines these treatment modalities further. Pretransplant donor antigen as 25 x 10(6) ultraviolet B-irradiated (12,000 joules/m2) donor spleen cells was given 7 days before heart transplantation through either the PV or systemic venous (IV) routes. On day 0, Lewis-to-Buffalo rat cardiac allografts were drained either into the PV or IV. Pretransplant PV donor antigen administration (p less than 0.005), but not by IV administration, significantly prolonged cardiac allograft survival across the strong RT 1 rat histoincompatibility barrier. Similarly PV, but not IV, drainage of the graft prolonged graft survival (p less than 0.005). Pretransplant IV antigen administration had no additive effect on PV drainage graft survival. In contrast, when pretransplant PV donor antigen was combined with PV drainage, 11 of 14 allografts (p less than 0.001) continued to function, free of rejection, after 150 days. Therefore for rat cardiac transplants a clearly synergistic graft-prolonging effect results when pretransplant PV donor antigen is combined with PV drainage of the allograts. These data clarify the potent tolerogenic effects of alloantigen not only administered into the PV but also continuously shed intraportally so that it is first processed by the liver.

Animals↗
PubMed1989

Multiple plasma exchanges successfully maintain a young adult patient with Crigler-Najjar syndrome type I.

Plasmapheresis has been shown to reduce total and free bilirubin levels in acute exacerbations of Crigler-Najjar syndrome, type I (CNS-TI), but its effectiveness in long-term management has not been reported. An 18-year-old (yo) male with CNS-TI, who required prolonged daily high-intensity phototherapy to prevent cerebral nervous system symptoms, developed increasingly frequent bouts of confusion, nausea, and vomiting associated with free bilirubin concentrations (fbcs) greater than 10-15 nmol/L. Pending consideration of orthotopic liver transplantation, plasma exchange (approximately 3 liters per procedure) was begun in 12/84 using the IBM/COBE 2997 with 5% albumin as replacement fluid. Frequency of treatments was guided by twice weekly fbcs, with plasma exchange for fbc greater than 10-15 nmol/L. Pre-exchange and postexchange fbcs ranged from 27.5 to 11 nmol/L and 9.2 to 2 nmol/L, respectively. Seventy-two exchanges were performed over a 28 month period. Irreversible CNS damage did not occur, and the patient underwent successful liver transplantation in April of 1987, with complete correction of his metabolic disorder. He remains well 18 months following transplantation.

Adolescent↗
PubMed1989

The effect of portacaval shunt on delayed-hypersensitivity responses following antigen feeding.

The antibody responses to ingested antigens are normally enhanced following a portacaval shunt (PCS), but the cell-mediated immune response has not been examined. It is also known that prior feeding induces tolerance to soluble protein antigens. This study examines the effect of PCS on oral cell-mediated tolerance. Normal Lewis rats (n = 16) and those (n = 10) with an end-to-side portacaval shunt surgically created 7 days earlier were fed either 200 mg soluble ovalbumin (OVA) or water by daily gastric gavage for 7 days. One week later, all animals were challenged subcutaneously with 250 micrograms OVA admixed in complete Freund's adjuvant. Twenty-one days later, delayed-hypersensitivity (DTH) responses were measured 24 hr after injection of 100 micrograms OVA (in media), or an irrelevant antigen (SRBCs), into the pinna of the ear. The intensity of the response was reflected by the increment in ear thickness, as well as the histological intensity of the mononuclear cell infiltrate. Oral administration of OVA significantly and specifically abrogated the DTH response to subsequent challenge with OVA (P less than 0.001). This DTH hyporesponsiveness was significantly reversed by the creation of a PCS (P less than 0.001). We conclude that the initial processing of ingested antigen within the liver is essential for the development of oral cell-mediated immune tolerance.

Administration, Oral↗