PubMed Health⌕ Search

Biomedical subjects

I Lloyd

Publications and source records attributed to I Lloyd.

6 recordsLinked to original sources
PubMed1993

The generation of a humanized, non-mitogenic CD3 monoclonal antibody which retains in vitro immunosuppressive properties.

CD3 antibodies are proven immunosuppressants capable of reversing transplant rejection episodes. Their general application has been limited both by their immunogenicity and, in particular, by the "first-dose" cytokine-release syndrome experienced by patients after the initial administration of antibody. We have produced a set of variants of the humanized YTH 12.5 CD3 monoclonal antibody (mAb) (Routledge et al., Eur. J. Immunol. 1991. 21: 2717) bearing different human heavy (H) chain constant regions, with the intention of finding a form of the antibody that is not able to activate T cells. Comparison of the variants having gamma 1, gamma 2, gamma 3 and gamma 4 H chains in a competitive binding assay showed that antibody avidity was not affected by IgG subclass. Using a sensitive indicator of FcR binding activity (the capacity of the CD3 mAb to redirect cytotoxic T cells to kill the monocytic cell line U-937) we demonstrated a functional hierarchy of gamma 1 = gamma 4 > alpha 2 =/> gamma 3 mb >> gamma 2. An aglycosyl version of the gamma 1 CD3 mAb, produced by site-directed mutagenesis (Asn297 to Ala), still had considerable activity in this assay (intermediate to the gamma 1 and alpha 2 CD3 mAb), albeit at a level approximately 10-fold lower than that of the parental gamma 1 form. When we tested their ability to stimulate T cell proliferation in vitro in the presence of 5% human serum, all of the wild-type immunoglobulin isotypes were found to be active, although there were T cell donor-dependent variations in the extent of the responses. The aglycosyl gamma 1 mAb was, however, completely non-mitogenic in all of ten donors tested, unless the assay was performed in IgG-free medium. Despite being non-stimulatory, this mAb was also able to inhibit the mixed lymphocyte reaction responses of both naive and primed T cells. Comparison of the gamma 1 and aglycosyl gamma 1 mAb in an experimental mouse model for CD3 mAb-induced cytokine release indicated that removal of the carbohydrate moiety from the gamma 1 constant region reduced the in vivo tumor necrosis factor-alpha response by a factor of at least 16-fold. These data suggest that the aglycosyl gamma 1 CD3 mAb is a promising candidate for immunosuppressive therapy without "first dose" side effects.

Animals↗
PubMed1991

A humanized monovalent CD3 antibody which can activate homologous complement.

The rat monoclonal antibody (mAb) YTH12.5, specific for the CD3 antigen complex on human T cells has been modified in order to improve its efficacy in human therapy. With the aim of rendering it less immunogenic, it has been humanized using the method of framework grafting. During this process sequence analysis of the YTH12.5 VL gene indicated that it was of the lambda subclass, however, it was markedly dissimilar from previously published rat and mouse V lambda gene sequences and may represent a new V lambda gene family. The humanization of this light chain represents the first successful reshaping of a lambda light chain V region. To improve the effector function of the antibody we have created a monovalent form (1 Fab, 1 Fc) using a novel method involving the introduction of an N-terminally truncated human IgG1 heavy chain gene into cells producing the humanized CD3 mAb. Comparison of the mono- and bivalent humanized mAb in a complement-mediated cell lysis assay revealed that the monovalent antibody mediated lysis of human T cell blasts whereas the bivalent form did not. The availability of a humanized, complement-fixing CD3 mAb may improve opportunities for human therapy, in the management of organ rejection, autoimmunity and the treatment of T cell lymphoma.

Amino Acid Sequence↗
PubMed1983

A comparison of low-risk pregnant women booked for delivery in two systems of care: shared-care (consultant) and integrated general practice unit. I. Obstetrical procedures and neonatal outcome.

Samples of records of comparable low-risk pregnant women booked for delivery in an integrated general practice unit (GPU) and a consultant (or shared-care) system were derived from a computer tape of all 5005 births which occurred at the John Radcliffe Hospital in 1978. Induction of labour, epidural analgesia and forceps delivery were all less frequently carried out in women booked for delivery in the GPU. Infants of multiparous women were more often intubated in the shared-care system (3%) than in the GPU (0%); rates in infants of nulliparous women were similar (approx. 7%) in the two systems. These data suggest that short-term outcomes are as good for GPU-booked low-risk women and their infants as for comparable women booked in consultant or shared-care.

Adolescent↗
PubMed1983

A comparison of low-risk pregnant women booked for delivery in two systems of care: shared-care (consultant) and integrated general practice unit. II. Labour and delivery management and neonatal outcome.

A random sample of low-risk pregnant women were equally divided into four groups of 63 nulliparae and multiparae each booked for care in a integrated general practice unit (GPU) and a shared-care (consultant) system. Selection criteria included only women who were admitted because they were in spontaneous labour or thought they were. Nulliparous women booked for shared-care came into hospital at a less advanced state of cervical dilatation than those booked for the GPU and spent longer (11 compared with 8 h) in hospital before delivery; the comparable durations in multiparae were 6 and 4 h. Both the first and second stages of labour were longer in the GPU-booked women but they received less pethidine and fewer had epidural analgesia; they received less electronic fetal monitoring, augmentation and forceps delivery, and fetal distress was diagnosed less often. The 1-min Apgar score was less than or equal to 6 in 17.5% of infants of nulliparae booked for the shared-care system compared with 1.6% of those booked for the GPU. The intubation rate of infants of nulliparae was 11% in the shared-care system compared with no intubations in the GPU. These comparisons demonstrate the simplicity and safety of delivery of low-risk women in the GPU as compared with deliveries of similar women in a shared-care (consultant) unit.

Adolescent↗