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[Therapy with plasmapheresis and lymphoplasmapheresis combined with immunosuppressive agents in 2 cases of intractable juvenile rheumatoid arthritis].

Two cases of JRA refractory to NSAID' steroids and long-acting drugs were successfully treated with plasmapheresis and combined lympho- and plasma-apheresis respectively. Case 1. A 8 year old female child who had been suffering from systemic JRA for 6 years received a course of three plasmapheresis followed by a 6 month cycle of azathioprine. Clinical and laboratory remission was promptly achieved and is still present after 18 months. Case 2. A 12-year old boy affected by poliarticular JRA received a course of 4 plasmapheresis followed by a 6 month cycle with azathioprine. The opportunity of performing plasma or lymphoplasmapheresis reinforced by immunosuppressive drugs such as azathioprine or methotrexate at low doses in refractory cases of JRA is discussed.

Arthritis, Juvenile↗
PubMed1983

Detection of pregnancy associated alpha 2-glycoprotein (alpha 2-PAG), an immunosuppressive agent, in IgA producing plasma cells and in body secretions.

Using a combined indirect immunoperoxidase (PAP)/direct immunofluorescence (IF) staining technique, pregnancy associated alpha 2-glycoprotein (alpha 2-PAG) has been shown to be present solely in the IgA producing plasma cells. alpha 2-PAG was undetectable in plasma cells synthesizing any of the other immunoglobulin isotypes (IgG, IgM, IgD and IgE). Furthermore, we have observed increased numbers of alpha 2-PAG positive cells in sites recognized for their local IgA production e.g. lactating breast, salivary gland, respiratory and gastrointestinal mucosae. In support of this cellular association with IgA, alpha 2-PAG was measured by enzyme immunoassay in colostrum, breast milk, saliva, jejunal secretions, bile and urine. The relevance of this novel and preferential association of immunosuppressive alpha 2-PAG with IgA is discussed with regard to the regulation of gut immunoresponsiveness.

Adult↗
PubMed1983

Difference in effect of single immunosuppressive agents (cyclophosphamide, CCNU, 5-FU) on peripheral blood immune cell parameters and central nervous system immunoglobulin synthesis rate in patients with multiple sclerosis.

Cyclophosphamide (CY), 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) and 5-fluorouracil (5-FU) were given in single course schedules to chronic progressive multiple sclerosis (MS) patients clinically stable for 6 months. The following peripheral immune cellular parameters were measured before, during and after each drug administration: white blood count (WBC), polymorphonuclear count (PMN), lymphocyte count, percentage of T cells, T cell response to phytohaemagglutinin (PHA), percentage of B cells, percentage of cells bearing receptors for the Fc portion of immunoglobulin (% FcR cells), killer (K) cell activity defined by antibody-dependent cellular cytotoxicity (ADCC), and natural killer (NK) cell activity. Central nervous system (CNS) immunoglobulin G (IgG) synthesis was also measured. The patients were followed carefully by both quantitative and qualitative methods for any change in their neurologic condition. Selective reduction in NK activity was observed with CY and 5-FU while no significant alteration was seen in %FcR cells and K activity. CY differed from 5-FU in reducing lymphocyte count and B cell percentage while 5-FU decreased the percentage of T cells. CCNU, but not the other drugs, reduced T cell proliferative response to PHA. In addition, CCNU, which is known to penetrate well into the nervous system, caused a modest reduction in CNS IgG synthesis, while 5-FU had an uncertain effect. Clinically the patients were unchanged or continued to progress in their disability. The results suggest an independence of the CNS immune from the systemic immune system in MS in response to many immunosuppressive drugs.

Adult↗
PubMed1979

Effect of immunosuppressive agents on the course of experimental syphilis in rabbits.

Rabbits infected intradermally with T. pallidum at four sites on the clipped back were treated with cyclophosphamide, 1 mg/kg body weight, twice before and every two days after inoculation for five months, or 5-fluorouracil 2.5 mg/kg body weight, according to the same regimen. Humoral response, as measured repeatedly by VDRL, FTA, and hemagglutination tests, was not affected by the application of the immunosuppressors. In contrast, the cell-mediated response, as determined by the Macrophage Migration Inhibition test was completely abolished in the treated rabbits. In the group of rabbits which were given immunosuppressors, syphilitic lesions appeared not only at the challenge sites, as usual, but also multiple multiform lesions developed over the entire dorsum after healing of the primary lesions. Taking into account the fact that abolishment of the cell-mediated response led to an aggravated course of the syphilitic infection, the results of these experiments were interpreted as indicating the protective role of the cell mediated response in syphilis.

Animals↗
PubMed1967

Biochemical studies with a new cytotoxic immunosuppressive agent, 3-acetyl-5-(4-fluorobenzylidene)-2,5-dihydro-4-hydroxy-2-oxothiophen (I.C.I. 47776).

1. A new cytotoxic agent, 3-acetyl-5-(4-fluorobenzylidene)-2,5-dihydro-4-hydroxy-2-oxothiophen (I.C.I. 47776), strongly inhibits protein and nucleic acid synthesis and, to a smaller extent, respiration in lymph-node cells and Landschütz ascites-tumour cells in vitro. 2. The activity of I.C.I. 47776 in vitro declines as the pH of the medium is increased and is inversely proportional to the concentration of serum in the medium. 3. The compound has no effect on the incorporation of leucine by a cell-free preparation from Landschütz ascites cells containing ATP and phosphoenolpyruvate. 4. I.C.I. 47776 stimulates glycolysis in suspensions of Landschütz ascites cells in the presence of excess of glucose but has no effect on glycolysis in suspensions of rat lymph-node cells. 5. I.C.I. 47776 markedly depresses ATP concentration in ascites cells in the absence of glucose but has no effect on the ATP concentration in the presence of glucose. The inhibition of protein synthesis by I.C.I. 47776 in ascites cells is, however, only partially reversed by the addition of glucose. 6. The ATP concentration of rat lymph-node cells incubated with I.C.I. 47776 in the absence of glucose is also markedly depressed but the addition of glucose increases the ATP concentration only slightly. Further, glucose has no effect on the inhibition of protein synthesis in lymph-node cells by I.C.I. 47776. 7. It is suggested that I.C.I. 47776 inhibits protein and nucleic acid synthesis in cell suspensions indirectly by acting as a mitochondrial poison. 8. The relevance of studies on the activity of I.C.I. 47776 in vitro to its cytotoxic and immunosuppressive action in vivo is discussed.

Journal Article↗
PubMed1993

Comparison of the effects of the immunosuppressive agents FK 506 and cyclosporin A on rat kidney mitochondria.

Interactions of FK 506 with renal cortical mitochondria have been investigated by measuring respiration, ATP net uptake and Ca2+/Pi-induced swelling. Both FK 506 and cyclosporin A (CsA) inhibit the succinate-supported state 3 and uncoupled respiration and are without effect on the glutamate/malate-supported state 3 and uncoupled respiration. FK 506, like CsA, inhibits net uptake of ATP, but, in contrast to CsA, is without effect on Ca2+/Pi-induced swelling.

Adenosine Triphosphate↗
PubMed1994

Metabolism of FK506, a potent immunosuppressive agent, by cytochrome P450 3A enzymes in rat, dog and human liver microsomes.

The oxidative metabolism of FK506 by liver microsomes and purified cytochrome P450 (P450) enzymes from rats, dogs and humans was studied. The major metabolite formed by liver microsomes from all species was 13-demethylated FK506, named M-I. In adult rats, liver microsomal metabolic activity toward FK506 was higher in males than in females and was stimulated by treatment with P450 3A inducers such as dexamethasone and phenobarbital. In a reconstituted monooxygenase system containing various forms of purified P450 3A enzymes, rat P450 3A2, dog P450 DPB-1 (a form of the P450 3A family) and human P450 3A4 catalyzed FK506 oxidation efficiently in the presence of cytochrome b5, a mixture of phospholipids (dilauroylphosphatidylcholine, dioleoylphosphatidylcholine and phosphatidylserine), and sodium cholate. Rat P450 2C6 and 2D1 and human P450 2CMP also metabolized FK506, with significant lower activity than the P450 3A enzymes, and other rat P450 1A, 2A, 2B, 2C and 2E families including C11 did not show catalytic activities for FK506. Anti-P450 3A2 and anti-P450 3A4 antibodies strongly inhibited FK506 oxidation catalyzed by rat and human liver microsomes, respectively. The formation rate of M-I correlated well with testosterone 2 beta- and 6 beta-hydroxylase activities in rat liver microsomes and with immunoquantified P450 3A4 content, nifedipine oxidase activity, and testosterone 6 beta-hydroxylase activity in human liver microsomes. These in vitro findings indicate that the P450 3A enzymes in liver microsomes from various species of animals, including human, play a major role in the first step oxidation of FK506.

Animals↗
PubMed1976

Generalized urticaria to cyclophosphamide: Type I hypersensitivity to an immunosuppressive agent.

A 6-yr-old white boy, Patient L. B., who was receiving cyclophosphamide (CY) for chemotherapy of a localized undifferentiated small cell sarcoma of the chest wall, developed generalized urticaria on three separate occasions immediately after CY administration. Serum samples were obtained 2 and 5 wk after the patient's last reaction and were examined for reaginic activity to the drug. Homocytotropic antibody activity to CY was found in the 2-wk postreaction sample by Prausnitz-Küstner type passive transfer skin testing to chimpanzees. This homocytotropic antibody was found to be of the IgE type, by means of an in vitro double-antibody coprecipitation assay measuring binding of free 14C-CY by specific immunoglobulin E and G fractions. Sera from 3 CY-treated patients who did not have adverse reactions to the drug and 6 normal, age-matched volunteers were used as control samples for the coprecipitation assay. None of the 3 CY-treated control patients had significant binding of 14C-CY by IgE when compared to normal individuals. However, it was found that all CY-treated patients had significant binding of 14C-CY by their IgG fraction when compared to normal subjects.

Binding Sites, Antibody↗