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Biomedical subjects

R Lord

Publications and source records attributed to R Lord.

At least 73 records · Page 4Linked to original sources
PubMed1995

Isolation of a 40 kDa immunoinhibitory protein induced by rat liver transplantation.

In certain combinations of donor and recipient rat strains, such as DA (RT1a) donors into PVG (RT1c) recipients, rejection after orthotopic liver transplantation (OLT) is overcome without immunosuppressive drugs, although other organs transplanted between these combinations are promptly rejected. The mechanisms involved in achieving drug-free liver allograft tolerance still remain poorly understood. In the present study, OLT (DA into PVG) serum from various postoperative times was analysed by sodium dodecyl sulphate polyacrylamide gel electrophoresis and two unique proteins of 40 kDa and 37 kDa were found to be in large concentrations in 60 day post-OLT serum. These proteins could only be detected at specific times after OLT in the DA into PVG combination and could not be detected in the serum of syngenically transplanted animals (DA into DA) and (PVG into PVG), rejector combinations (DA into LEW) requiring immunosuppressive treatment or induced by other organ transplants. When these proteins were purified and sequenced they were found to have an identical N-terminal sequence which is not listed in sequence databases. Mixed lymphocyte assays revealed that only the 40 kDa protein has a immunosuppressive capability which additionally appears to be donor specific. The 40 kDa protein will aid further in the understanding of how drug-free tolerance is attained in certain liver allografts and may also act as a marker of when treatment with conventional immunosuppressive drugs can be stopped in clinical OLT providing a homologue of the molecule can be found. This possibility appears likely as case reports already exist of patients who have successfully been able to cease treatment with such drugs.

Amino Acid Sequence↗
PubMed1995

The results of a phase II randomized trial comparing 5-fluorouracil and 5-fluorouracil plus alpha-interferon: observations on the design of clinical trials for androgen-independent prostate cancer.

The therapeutic benefit of chemotherapy in androgen independent prostate cancer is limited. 5-Fluorouracil has been reported to have modest antitumor activity in androgen independent prostate cancer. Although alpha-interferon is inactive as a single agent in prostate cancer, preclinical data indicate that it increases the in vitro cytotoxicity of 5-fluorouracil against a variety of malignant cells. We evaluated the relative antitumor activity and tolerance of 5-fluorouracil versus 5-fluorouracil plus alpha-interferon in 50 patients with histologically confirmed metastatic adenocarcinoma of the prostate. These patients had progressive disease in the presence of castrate levels of testosterone. A prospective randomized phase II open labeled trial was performed because of the difficulty in measuring responses in patients with metastatic prostate cancer. Of 23 patients treated with 5-fluorouracil alone and 28 treated with 5-fluorouracil plus alpha-interferon 17 and 23, respectively, were evaluable for response and toxicity, and 5 and 5, respectively, were evaluable for toxicity only. Only 2 of 17 (11.7%) and 4 of 23 (17%) patients, respectively, showed a greater than 50% decrease in serum prostate specific antigen (no significant difference). There was no difference in duration of response or duration of survival between the 2 groups (mean duration of response 8.64 and 6.17 weeks, respectively, and mean duration of survival 33.70 and 38.65 weeks, respectively). Both regimens caused significant morbidity (mucositis and neurotoxicity) and 3 treatment related deaths at the high 5-fluorouracil doses. 5-Fluorouracil alone and with alpha-interferon at the doses used have minimal antitumor activity against androgen independent prostate cancer and, therefore, should not be tested further in these patients. Androgen independent prostate cancer selected using our criteria is a rapidly progressive disease, and these patients are an ideal target population for phase II studies.

Adenocarcinoma↗
PubMed1995

Migration of donor cells into the thymus is not essential for induction and maintenance of systemic tolerance after liver transplantation in the rat.

In this study, we show that cells encoded by donor-type major histocompatibility complex (MHC) class I antigens effectively migrate into the thymus of the host after liver transplantation. However, the thymus is not essential for the induction and maintenance of tolerance after orthotopic rat liver transplantation (OLT). Liver allografted rats in the DA(RT1a) into PVG (RT1c) combination survived without immunosuppressive agents. The thymus of the host showed a transitory atrophy and returned to normal weight 4 weeks after OLT. Donor antigens were detected in the host thymus after OLT. Adult PVG rats that had been thymectomized 1 week before implantation of DA liver grafts showed liver graft survival without immunosuppression. DA heart grafts were heterotopically transplanted into the PVG thymectomized, liver-grafted rats 1-4 weeks after OLT. No rejection of the cardiac allografts was observed. Systemic tolerance was induced and maintained in the absence of the thymus.

Animals↗
PubMed1994

Induction of natural chimerism after retransplantation of the liver in rats.

Immunological aspects after orthotopic rat liver retransplantation (re-OLT) were examined in association with cell migration and mixed chimerism. At day 2 after the first orthotopic liver transplantation (day 0) in the combination of DA (MHC haplotype, RT1a) donor into PVG (RT1c) recipient, the grafted DA liver was removed and a new PVG liver was implanted into the same PVG recipient (re-OLT). In the PVG recipient at various times after the re-OLT, DA-derived antigen and cells were detected using a DA-specific anti-class I mAb R3/13 in conjunction with ELISA, immunoblotting, and immunohistochemistry. The level of soluble class I antigen, which had risen to 270 ng/ml after the first OLT, substantially decreased within 24 hr after re-OLT. Using immunoblotting, DA class I antigen was detected in the PVG recipient's lymphoid organs at day 3 after DA liver grafting and persisted for up to 21 days after the DA liver was replaced by a new PVG liver. Immunohistochemistry on sections of spleen from re-OLT rats showed that the level of migratory cells expressing DA class I correlated with the findings obtained by immunoblotting. While the DA-derived antigen and cells were detected in the re-OLT recipient, the DA-specific inhibition of mixed lymphocyte reaction was observed in re-OLT serum. Our results suggest that the implanted DA liver graft was the source of DA soluble class I antigen, but DA-derived antigen and cells detected in the re-OLT recipient organs could persist for a relatively long time under immunosuppression after the implanted DA liver was removed by re-OLT.

Animals↗
PubMed1994

A technique for complete thymectomy in adult rats.

50 open thymectomies were performed in adult rodents using intubation combined with a fibrin glue able to prevent hemorrhage and pulmonary air leakage. This method had a 100% success rate and lower mortality than the ordinal suction procedure. Although the conventional suction thymectomy has been widely used, the open thymectomy method would permit more complete thymectomies for immunological studies.

Animals↗
PubMed1993

Mice immunized with a synthetic peptide construct corresponding to an epitope present on a Plasmodium falciparum antigen are protected against Plasmodium chabaudi challenge.

Inhibitory monoclonal antibody (MoAb) 8E7/55 recognizes a parasitophorous vacuole membrane (PVM) antigen in Plasmodium falciparum. Previous studies have identified the epitope, DNNLVSGP, recognized by the MoAb. A synthetic peptide containing this sequence was synthesized and coupled to diphtheria toxoid (DT) and was found capable of generating antibodies when used as an immunogen in mice which recognize the native antigen exp-1. In this study we demonstrate the ability of the MoAb and antisera generated against the peptide construct to recognize a 54 kD PVM antigen in Plasmodium chabaudi. The P. chabaudi antigen is synthesized in trophozoites and released to the surrounding culture media outside the parasitized erythrocyte. Mice immunized with the peptide conjugate are protected when challenged with a lethal strain of P. chabaudi. Protection in the mice correlated with the antibody titre prior to challenge. If the PVM antigen from P. chabaudi is a homologue of exp-1 from P. falciparum, then these experiments may provide a guide to the antibody titres required in human trials before antibody mediated protection could be expected. The discovery that a PVM localized antigen is secreted into the surrounding in vitro culture media provides us with a valuable model system for further investigation of protein trafficking pathways in malaria-infected erythrocytes.

Amino Acid Sequence↗