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K J Wood

Publications and source records attributed to K J Wood.

At least 19 recordsLinked to original sources
PubMed1992

Isolated HLA-DP mismatches between donors and recipients do not influence the function or outcome of renal transplants.

The matching of donors and renal graft recipients for human leukocyte antigens A, B, and DR has been shown to exert beneficial effects on the outcome of transplantation. Until the advent of polymerase chain reaction amplification-based genotyping, the effect of HLA-DP compatibility on graft survival could not be thoroughly investigated. HLA-DP compatibility has been determined in three living-related transplants and 34 cadaveric transplants for donor-recipient pairs matched for HLA-DR and -DQ. The effect of DP mismatching on graft survival and function was assessed. No clear benefit from matching donor and recipient for HLA-DP could be discerned.

Base Sequence↗
PubMed1992

The effectiveness of pretreatment with soluble or membrane-bound donor class I major histocompatibility complex antigens in the induction of unresponsiveness to a subsequent rat renal allograft.

We have examined the ability of two physical forms of RT1.A class I molecules to induce immunologic unresponsiveness to renal allografts in the rat. Both preparations of class I MHC antigen were derived from rat liver. Class I MHC antigen was presented either as purified membrane-bound molecules incorporated into protein micelles or as a water-soluble preparation containing soluble RT1.A class I molecules. The amount of RT1.A class I contained in each preparation was compared with the amount of class I antigen expressed by whole viable liver cells by quantitative absorption analysis using F16.4.4.11 mAb. The results demonstrated that DA recipients pretreated with a single dose of 1.75 x 10(10) cellular equivalents or multiple doses of 5 x 10(9) cellular equivalents of purified LEW membrane-bound class I molecules, delivered in aggregated micelle form, accepted their LEW renal allografts indefinitely (MST greater than 100 days). In contrast, no prolongation of graft survival was observed using the liver cell cytosol preparation containing soluble RT1.A class I molecules (MST 10 days) at the concentrations tested (10(8) -3 x 10(8) cell equivalents). However, when preoperative treatment with single (greater than or equal to 5 x 10(7) cellular equivalents of soluble class I MHC antigen) or multiple doses (greater than or equal to 10(7) cellular equivalents per dose) of the liver cell cytosol preparation was combined with a subtherapeutic dose of CsA given postoperatively (day +2, 10 mg/kg), suppression of renal allograft rejection was achieved with long-term survival (MST greater than 100 days). The immunologic unresponsiveness observed in both cases was donor specific.

Animals↗
PubMed1992

Induction of transplantation tolerance in adults using donor antigen and anti-CD4 monoclonal antibody.

The T-cell-mediated immune response usually results in the rapid destruction of organ allografts transplanted between murine strains incompatible for major and minor histocompatibility antigens. This response may be modified by pretreatment with either donor-specific antigen or anti-CD4 monoclonal antibody. Previous work by others has shown that combined treatment of mice with soluble protein antigens and anti-CD4 monoclonal antibody can produce antigen-specific B cell unresponsiveness that continues long after the nonspecific immunosuppressive effect of the mAb treatment has resolved. Following this principle we have shown that adult C3H/He mice can be made specifically unresponsive to vascularized C57BL/10 cardiac allografts by pretreating the recipient with donor alloantigen under the cover of a brief course of mAb against CD4. A full-dose response analysis shows that the dose of mAb is critically important for the successful induction of tolerance. Tolerance induction using this protocol is dependent on treatment with donor major histocompatibility complex antigens and occurs in the presence of marked depletion but not complete elimination of the CD4+ T cell subset. The unresponsiveness to alloantigen is antigen specific, as determined by the ineffectiveness of third-party (C57BL/10) alloantigen when combined with anti-CD4 mAb to induce long-term survival of BALB/c allografts in C3H/He recipients. The tolerant state is specific and effective in the long-term as indicated by the specific acceptance of C57BL/10 skin grafts in recipients with surviving C57BL/10 cardiac allografts. This study provides a simple method for the successful induction of specific transplantation tolerance in the adult across a full H-2 major and minor antigen mismatch strain combination. The results illustrate the important role of the CD4 molecule in the T cell response to alloantigen in vivo and suggest possibilities for the therapeutic manipulation of complex immune reactions.

Animals↗
PubMed1992

Evidence that long-term cardiac allograft survival induced by anti-CD4 monoclonal antibody does not require depletion of CD4+ T cells.

Monoclonal antibodies that deplete cells carrying their target antigen are being used increasingly for immunosuppression in clinical and experimental transplantation. We have characterized a panel of rat antimouse CD4 monoclonal antibodies with the aim of establishing, in a vascularized organ transplant model, whether prolonged graft survival can be induced without recipient T cell depletion. The spatial relationship of the epitopes recognized by the anti-CD4 mabs was established. Mabs of the IgG2b isotype were found to profoundly deplete CD4+ T cells in vivo, whereas IgG2a mabs did not. The IgG2b anti-CD4 mab YTS191 and the IgG2a mab KT6 both blocked proliferation of C3H/He leukocytes in mixed leukocyte culture. Potent suppression of rejection and indefinite survival of cardiac allografts, mismatched for both major and multiple minor histocompatibility antigens (C57BL/10, H-2b into C3H/He, H-2k), was achieved with the IgG2b anti-CD4 mab YTS191 that depleted CD4+ T cells, (n = 9, median survival time (MST) greater than 100 days, P less than 0.001). The non-depleting IgG2a anti-CD4 mab, KT6, which had been shown to recognize and epitope on the CD4 molecule closely related to that recognized by YTS191 and to block comparably in MLC, was also shown to be capable of producing long-term cardiac graft survival in this strain combination (n = 6, MST greater than 100 days P less than 0.001). The kinetics of the KT6 therapy on the blocking of the CD4 molecule in vivo were investigated and shown to correlate with the effectiveness of the mab in prolonging graft survival.

Animals↗
PubMed1991

Peripheral tolerance to alloantigen results from altered regulation of the interleukin 2 pathway.

Tolerance to alloantigen may be induced in rats by administration of blood followed by transplantation of a renal allograft. The mechanism of this tolerance was investigated by directly analyzing the functional activity of graft-infiltrating cells. We have previously shown cytotoxic T lymphocyte infiltration of, and major histocompatibility complex induction on, grafts of tolerant animals. We now report that cells isolated from the grafts of tolerant rats show a reduced expression of the p55 interleukin 2 receptor (IL-2R) chain on the cell surface compared with that seen on the cells of untreated animals. Scatchard analysis further reveals low expression of high affinity IL-2R. This is due to reduced transcription of both IL-2R alpha and beta chain mRNAs and results in a reduced ability of cells to proliferate in response to IL-2. Cells isolated from tolerant animals are unable to make biologically active IL-2 in culture, whereas cells from untreated animals make high levels. This is not reflected at the mRNA level as the IL-2 gene is induced in both tolerant and untreated animals to similar levels. The induction of tolerance is abrogated by administration of recombinant IL-2 to animals at the time of transplantation. Thus, we conclude that an altered regulation of the IL-2 pathway results in tolerance in these alloantigen-treated and transplanted animals.

Animals↗
PubMed1991

Rat brain xenografts reverse hypogonadism in mice immunosuppressed with anti-CD4 monoclonal antibody.

This study examines the effect of immunosuppression with monoclonal antibodies (MAb) against the murine CD4 (L3T4), a cell surface glycoprotein expressed primarily on helper T-lymphocytes, on the viability and function of rat neural xenografts placed in the third ventricle of hypogonadal (hpg) mice. The hpg mouse fails to synthesize hypothalamic gonadotrophin releasing hormone (GnRH) and consequently there is a drastic reduction in pituitary gonadotrophic hormone content and a failure of postnatal gonadal development (Cattanach et al. 1977). Three groups of male hpg mice received xenografts of day 1 post natal rat preoptic area (POA) tissue, a source of GnRH neurons, to their third ventricle. Those immunosuppressed with anti-CD4 MAb all showed surviving graft tissue thirty days post-transplant and half of this group had enlarged testes with all stages of spermatogenesis. In those hpg mice which were injected with saline alone, or with an anti-CD8 (Lyt-2) antibody there was no xenograft survival. These results suggest that the injection of monoclonal antibodies against the T-helper subset may provide an alternative means of immunosuppression aimed at the enhancement of survival of tissue grafts in the CNS.

Animals↗
PubMed1991

Alternative approaches for the induction of transplantation tolerance.

The immunosuppressive drugs currently in use in clinical transplantation are undoubtedly very effective at controlling graft rejection. However, their use is associated with a large number of side-effects, both immunological and non-immunological, particularly in the longer term. From an immunological point of view, the major disadvantage of these agents is that their mode of action is immunologically non-specific, resulting in blanket or pan-immunosuppression of the recipient's immune system. Thus, not only is the recipient's immune response against the organ graft suppressed, but responses to all other antigenic stimuli such as viral infections are also prevented. The transplant recipient can therefore become severely immunocompromised as a result of the drug therapy and is susceptible to opportunistic infections and an increased incidence of cancer. One of the aims for the design of new immunosuppressive therapy is to develop protocols that are both effective and immunologically specific, such that only the immune response to the transplanted organ is suppressed. The optimal approach would be to induce tolerance to the donor histocompatibility antigens before transplantation, permanently paralysing the ability of the recipient's immune system to mount a rejection response against the graft. Some of the approaches for the induction of immunological tolerance currently being explored in clinical transplantation will be discussed. These include total lymphoid irradiation (TLI) and donor bone marrow transfusion combined with anti-lymphocyte globulin (ALG) post-transplantation. In addition some new approaches for the induction of tolerance before transplantation currently being investigated in experimental systems will be presented.

Animals↗
PubMed1991

Transplantation tolerance.

New experimental protocols for the induction of transplantation tolerance continue to be developed. In the past year, encouraging data have been reported from a clinical trial using a protocol specifically designed to induce tolerance to the histocompatibility antigens of the kidney donor. Progress has also been made in our understanding of the mechanisms responsible for the induction and maintenance of tolerance to alloantigens in vivo; it is becoming increasingly clear that more than one mechanism can be involved, particularly at different phases in the response.

Graft Enhancement, Immunologic↗
PubMed1991

The combined effect of perioperative donor spleen cells or KCl-extracted antigen and cyclosporine on renal allograft survival in the rat.

The effects of using perioperative cyclosporine in conjunction with pretreatment with donor spleen cells or 3M KCl solubilized extracts of donor antigen were investigated in a LEW-to-DA rat renal allograft model. Cyclosporine given orally in a dose of 10 mg/kg/day around the time of transplantation (days -1, 0, +1), did not prolong renal allograft survival (median survival time [MST]--10 days). However when used in combination with pretreatment with either 10(8) donor spleen cells (1 day before transplantation), or 10(5) donor spleen cells (7 days before transplantation), pretreatment regimens that were in themselves ineffective, DA recipients accepted Lewis renal allografts indefinitely (MST greater than 100 days). Soluble antigen was prepared by 3M KCl extraction from donor spleen cells. Absorption assays were used to quantify the amount of class I major histocompatibility complex antigen in the preparation, and amounts of antigen equivalent to that expressed by 10(6)-10(8) donor spleen cells were used for pretreatment. These soluble antigen preparations given either 1 or 7 days before transplantation with or without perioperative cyclosporine did not prolong allograft survival of either homozygous or heterozygous donors (MST 10 days).

Animals↗
PubMed1991

C-reactive protein levels in serum: a rapid enzyme immunoassay.

A simple and rapid competitive-inhibition enzyme linked immunoassay for serum C-reactive protein (C-RP) is described. The assay has a working range of 4.4-700 mg/l of C-RP, uses two serum dilutions and requires only 90 min to perform. Comparisons are presented between this assay and three commercially-available kits. The assay performs as well as the best of these kits but with added advantages of speed, ease of use and increased working range.

Binding, Competitive↗
PubMed1990

Transplantation tolerance with monoclonal antibodies.

Monoclonal antibodies (Mabs) are powerful tools for manipulating the immune system as they are capable of triggering, amplifying or suppressing immune responses. The resultant effect of monoclonal antibody (MAb) manipulation is related not only to the antigenic specificity of the antibody used, but also to its structural properties and mechanism of action. There has been much interest in using MAbs to control or regulate immune responses in vivo and they are now commonly used successfully in clinical transplantation for the treatment of graft rejection. The induction of transplantation tolerance in adult recipients is an important goal of transplantation research. The development of MAbs for immunotherapy has allowed new approaches for the induction of tolerance to vascularised organ grafts to be explored.

Animals↗