Search

The stimulation of a draining lymph node by the injection of a substance possessing adjuvanticity leads to a marked increase in the influx of lymphocytes into the node. The influx of cells has been followed in experimental mice injected intravenously with 51Cr-labelled normal mesenteric lymph node cells. The increase in size of the draining node is not due to an increased blood volume. [ABSTRACT FROM AUTHOR]

The histological accompaniments of adjuvant activity were studied in popliteal nodes of CBA mice at various intervals after footpad injection. Substances tested possessed either extrinsic adjuvanticity but little or no antigenicity (alum, vitamin A alcohol), antigenicity but no extrinsic adjuvanticity (bovine γA-like globulin), both (Freund's complete adjuvant, killed B. pertussis organisms, alum-precipitated BGG), or neither (paraffin oil BP). Substances possessing extrinsic adjuvanticity produced marked persistent enlargement of the draining lymph node, with prominent expansion, hypercellularity and blast transformation in the paracortical areas by the 4th day after injection, This was followed by germinal centre formation and medullary plasmacytosis occurring between the 4th and 10th day. Substances possessing little or no antigenicity produced a feeble germinal centre response and minimal medullary expansion. Bovine γA-like globulin, which lacks extrinsic adjuvanticity, produced a prominent germinal centre and medullary response but a minimal paracortical response. Only mild, transient lymph node enlargement, lasting 1-2 days, was seen alter paraffin oil BP. Passive immunization of CBA mice with CBA anti-pertussis hyperimmune serum inhibited the adjuvant action of pertussis, and diminished and delayed the histological changes in the draining lymph node. These data suggested that paracortical expansion and hyperplasia were characteristic histological accompaniments to the injection of substances with extrinsic adjuvanticity. Because paracortical hypercellularity was observed in some instances to precede blast cell transformation, it is suggested that paracortical expansion induced by adjuvants is partly due to an augmented cellular traffic, with a net flux of recirculating lymphocytes into these areas. [ABSTRACT FROM AUTHOR]

Summary. The effects of heterologous anti-lymphocyte serum (ALS) were studied in a syngeneic cell transfer system, in which lymph node cells from donor CBA mice were labelled in vitro with 51Cr and transferred intravenously into syngeneic recipients. Labelled cells treated in vitro with ALS were unable to migrate to lymph nodes or spleens of recipients, as did normal cells, but instead distributed themselves very similarly to cells which had been killed by exposure to heat. It is thus likely that cells treated in vitro with ALS are killed after transfer by the cytotoxic action of ALS mediated by the complement of the recipient. ALS administered directly to the recipients of labelled lymphocytes could also reduce their uptake into lymphoid tissue; however, the magnitude of this effect appeared to be critically dependent upon the timing of the antiserum dose with respect to the labelled cell dose. ALS given immediately prior to labelled cells showed the greatest effect, while treatment given either 24 hours before or after the labelled cells was much less effective. While with prior treatment the reduced effect could be due to a fall off in antibody titre during the interval between the dose of antiserum and cells, in the latter situation no drop in titre would have occurred. It thus seems that lymphocytes that have already established themselves in lymphoid tissue may be less susceptible to the action of ALS. ALS given chronically to lymphoid cell donors resulted in a population of cells which upon transfer to normal recipients were distributed differently from either normal or NRS-treated donor cells. These data support the hypothesis that the effects of ALS may be exerted preferentially on circulating lymphocytes, and that ALS may act to selectively reduce the representation of this cell type in lymphoid tissue. [ABSTRACT FROM AUTHOR]

The 'activity' of rabbit anti-mouse ALS was measured in terms of its power to prolong the life of A-strain homografts on CRA mice. Antisera raised by lymphocytes from mice of other strains were active in CBA mice, and conversely antisera raised by CBA lymphocytes were active in mice of other strains. All active sera were cytotoxic to mouse lymphocytes in the presence of mouse complement, but not all cytotoxic sera were active. ALS raised in species (chicken, duck) of which the sera do not bind with mouse complement were inactive in mice. Neither cytotoxicity nor the power to circumvent graft-versus-host reactions give adequate measures of the activity of impure antisera. Good antiserum ('two-pulse' ALS) for use in mice could be raised in New Zealand White rabbits by the intravenous injection of 109 mouse thymocytes on two occasions 14 days apart, followed by bleeding out 7 days after the second injection. Further injections of antigen increased the titre of undesirable contaminants in ALS (e.g. red cell agglutinins) but usually did not increase (and sometimes lowered) activity. ALS raised with adjuvants, though powerful, was highly toxic and required extensive absorption. [ABSTRACT FROM AUTHOR]

Background: Non-alcoholic steatohepatitis (NASH) is a progressive form of non-alcoholic fatty liver disease (NAFLD) associated with steatosis, hepatocellular injury, inflammation and fibrosis. In a Phase 2 trial in adults with NASH (NCT02912260), resmetirom, an orally administered, liver-targeted thyroid hormone receptor-β selective agonist, significantly reduced hepatic fat (via imaging) and resolved NASH without worsening fibrosis (via liver biopsy) in a significant number of patients compared with placebo., Aims: To present the design of the Phase 3 MAESTRO clinical programme evaluating resmetirom for treatment of NASH (MAESTRO-NAFLD-1 [NCT04197479], MAESTRO-NAFLD-OLE [NCT04951219], MAESTRO-NASH [NCT03900429], MAESTRO-NASH-OUTCOMES [NCT05500222])., Methods: MAESTRO-NASH is a pivotal serial biopsy trial in up to 2000 adults with biopsy-confirmed at-risk NASH. Patients are randomised to a once-daily oral placebo, 80 mg resmetirom, or 100 mg resmetirom. Liver biopsies are conducted at screening, week 52 and month 54. MAESTRO-NAFLD-1 is a 52-week safety trial in ~1400 adults with NAFLD/presumed NASH (based on non-invasive testing); ~700 patients from MAESTRO-NAFLD-1 are enrolled in MAESTRO-NAFLD-OLE, a 52-week active treatment extension to further evaluate safety. MAESTRO-NASH-OUTCOMES is enrolling 700 adults with well-compensated NASH cirrhosis to evaluate the potential for resmetirom to slow progression to hepatic decompensation events. Non-invasive tests (biomarkers, imaging) are assessed longitudinally throughout, in addition to validated patient-reported outcomes., Conclusion: The MAESTRO clinical programme was designed in conjunction with regulatory authorities to support approval of resmetirom for treatment of NASH. The surrogate endpoints, based on week 52 liver biopsy, serum biomarkers and imaging, are confirmed by long-term clinical liver-related outcomes in MAESTRO-NASH (month 54) and MAESTRO-NASH-OUTCOMES (time to event)., (© 2023 Madrigal Pharmaceuticals. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Granulocytes from patients with chronic myelogenous leukaemia (CML) have been previously shown to have aberrant sialylation of membrane glycoproteins. We have examined the granulocytes from CML patients receiving intermittent chemotherapy to determine the relationship of the oligosaccharide changes to treatment. Compared to cells from non-leukaemic patients, granulocytes from untreated CML patients showed less adherence to nylon wool, decreased reactivity with peanut lectin, and decreased binding of the synthetic chemotactic peptide formyl-methionine-leucine-phenylalanine (FMLP). Granulocytes from CML patients treated with chemotherapy showed nylon wool adherence, peanut lectin reactivity and FMLP binding comparable to non-leukaemic cells. Chemotherapeutic agents may interfere with oligosaccharide synthesis with a resulting change in the composition of cell surface glycoconjugates.