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S Cobbold

Publications and source records attributed to S Cobbold.

At least 37 records · Page 2Linked to original sources
PubMed1993

The use of monoclonal antibodies to achieve immunological tolerance.

Monoclonal antibodies are potentially useful immunosuppressive agents. Short courses of CD4/CD8 monoclonal antibody can be used to guide the immune system of experimental animals to accept organ grafts and to arrest autoimmunity. This reprogramming is accompanied by potent T-cell dependent, 'infectious' regulatory mechanisms. A goal for therapeutic immunosuppression should be to understand and harness these innate immunoregulatory mechanisms.

Animals↗
PubMed1993

Monoclonal antibodies for the induction of transplantation tolerance.

Non-lytic antibodies to CD4 and certain other T cell adhesion receptors can guide the immune system to become tolerant to foreign antigens, and to regain tolerance in autoimmunity. Tolerance is maintained lifelong through the action of regulatory T cells that in turn can influence naive T cells to acquire the same regulatory properties. A fuller understanding of the molecular basis of infectious tolerance could lead to the design of better immunosuppressive protocols.

Animals↗
PubMed1992

Tolerance in the mouse to major histocompatibility complex-mismatched heart allografts, and to rat heart xenografts, using monoclonal antibodies to CD4 and CD8.

Mice given a single short course of anti-CD4 and anti-CD8 monoclonal antibodies (mAb) became tolerant of major histocompatibility complex (MHC)-incompatible vascularized heart allografts in a donor- and organ-specific manner. T cell depletion was not important, as blocking antibodies were equally effective. Anti-CD4 antibody therapy alone was sufficient to establish tolerance. Anti-CD8 mAb therapy alone was associated with poor recipient survival, although survivors were rendered tolerant. A second donor-type heart allograft to the neck was always accepted in recipients which had carried the first abdominal heart allograft for over 120 days, with the first heart also continuing to function. However, donor-type skin grafted at 100 days was sometimes rejected, albeit chronically. Those recipients that accepted the donor-type skin were able to reject third-party skin grafts mismatched at the MHC, or over multiple minor differences alone. Thus, the tolerance induced appeared to be donor and tissue specific, although spreading in some cases to tolerance of skin. Similarly donor-specific tolerance was found when xenogeneic PVG rat hearts were grafted into CBA/Ca mice using the same protocols of anti-CD4 plus anti-CD8 mAb. Resolution of the mechanisms underlying these forms of tolerance may permit the design of improved immunosuppressive protocols for human organ transplantation.

Animals↗
PubMed1990

Characterization of effector cells of graft vs leukemia following allogeneic bone marrow transplantation in mice inoculated with murine B-cell leukemia.

It is now widely accepted that immunocompetent lymphocytes in allogeneic bone marrow grafts exert an antileukemic effect that contributes to the cure of leukemia. Graft vs leukemia (GVL) effects independent of graft vs host disease were investigated in allogeneic bone marrow chimeras tolerant of host and donor alloantigens. The role of Thy1.2, L3T4 and Lyt2 T lymphocytes as effector cells of GVL were investigated in (BALB/c x C57BL/6)F1 mice inoculated with murine B-cell leukemia and subsequently conditioned with total lymphoid irradiation and cyclophosphamide (200 mg/kg). Mice were reconstituted with C57BL/6 bone marrow cells depleted of well-defined T-cell subsets or enriched for stem cells by the soybean agglutination method. Detection of residual tumor cells, an indicator for efficacy of GVL, was carried out by adoptive transfer of peripheral blood or spleen cells obtained from treated chimeras into secondary naive BALB/c recipients at different time intervals following bone marrow transplantation. Treatment of the primary marrow inoculum with monoclonal anti-Thy1.2 or anti-Lyt2 abolished the GVL effects and all secondary BALB/c recipients developed leukemia within 60 days. On the other hand, the treatment with monoclonal anti-L3T4 did not influence the effect of GVL and all treated recipients remained without leukemia. The data suggest that T cells may mediate GVL effects in the absence of graft vs host disease and in circumstances where tolerance to conventional alloantigens is elicited. Effector cells of GVL across the major histocompatibility complex (MHC) in the murine B-cell leukemia tumor model system appear to be Thy1.2+ Lyt2+ L3T4-. Induction of GVL effects by allogeneic cells tolerant of host MHC suggests that these effects may be independent of graft vs host disease.

Agglutinins↗
PubMed1989

Induction of classical transplantation tolerance in the adult.

Transplantation tolerance across histoincompatibilities in multiple non-H-2 minors (B10.BR into CBA/Ca) and "minor" plus H-2D (B10.A into CBA/Ca) antigens has been achieved successfully by combined adult bone marrow transplantation and treatment with CD4 and CD8 mAbs. The tolerant state was confirmed by permanent acceptance of donor strain skin grafts, and in vitro unresponsiveness to donor cells. Tolerance was associated with partial donor chimerism to various degrees. Tolerance to minor transplantation antigens induced in this manner was restricted to recipient-type MHC. The possibility was raised that tolerance resulted, at least in part, from clonal anergy rather than deletion.

Animals↗
PubMed1989

The improved lytic function and in vivo efficacy of monovalent monoclonal CD3 antibodies.

A series of hybrid-hybridomas were derived by the cell fusion of a CD3 antibody-secreting hybridoma with other Ig-producing cell lines. The Ig molecules secreted by these hybrid-hybridomas were fractionated by ion-exchange chromatography, and fractions containing monovalent CD3 antibodies were tested for complement-mediated lysis of T cells. Two monovalent CD3 antibodies with mixed heavy chain isotypes were very poor in lysis but, in contrast, a monovalent antibody possessing two identical rat gamma 2b heavy chains but two non-identical light chains was found to be more lytic with human complement than the parental bivalent CD3 antibody. The difference in lysis was not readily explicable in terms of a difference in complement activation at the level of C1q binding or cell-associated C3. A highly purified batch of this lytic monovalent CD3 antibody was prepared in a form suitable for in vivo therapy. In a preliminary clinical study in one patient with a T lymphoma in leukemic phase this monovalent CD3 antibody was found to be very effective in depleting CD3+ tumor cells in the peripheral blood and bone marrow. The cells in the peripheral blood were completely cleared and there was no evidence for antigenic modulation. In addition the antibody was able to reverse cell-mediated kidney rejection in three kidney graft patients. These results suggest that monovalent antibody may be effective in vivo as well as in vitro and that a fuller clinical evaluation is justified.

Adolescent↗
PubMed1989

Cultured keratinocyte grafts are recognized, but not rejected by CD8+ T cells in vivo.

It has been shown in the mouse that cultured keratinocyte allografts [fully major histocompatibility complex (MHC) mismatched] survive for at least 100 days without evidence of rejection. In an attempt to analyze the immune mechanisms underlying this phenomenon we have investigated the induction of tolerance to such grafts. Primary cultures of BALB/c keratinocytes were prepared using irradiated 3T3 feeder cells, and the cultured cell sheets were grafted, using a silicone transplantation chamber, onto CBA recipients. After the cultured grafts had been in place for 4-6 weeks full-thickness tail skin from BALB/c donors was grafted onto the dorsal flank opposite the cultured graft. The median graft survival time of these full-thickness allografts was 15.5 days compared to 13 days in the control group. These data show that in the absence of Langerhans cells and MHC class II expression, keratinocytes expressing class I and minor histocompatibility antigens induce a prolonged survival of full-thickness skin allografts. The results from experiments in which T cell subsets were depleted in vivo suggest that CD8+ cells (a) recognize the class I alloantigens of the cultured graft, (b) do not reject the cultured graft and (c) do not progress further in their maturation pathway. We propose that these CD8+ T cells might have been partially primed by receiving only the first signal of activation and that they may be equivalent to "poised" cytotoxic T cells. These CD8+ cells can reject non cultured full-thickness skin grafts, and do so more effectively after removing CD4+ cells.

Animals↗
PubMed1989

Depletion of L3T4+ and Lyt-2+ cells by rat monoclonal antibodies alters the development of adoptively transferred experimental autoimmune thyroiditis.

To delineate the contribution of L3T4+ and Lyt-2+ cells in the pathogenesis of experimental autoimmune thyroiditis (EAT), synergistic pairs of monoclonal antibodies (mAb) to the T cell subsets were used in conjunction with the adoptive transfer of mouse thyroglobulin (MTg)-activated cells from immunized mice. Initial experiments verified the important role of L3T4+ cells in the transfer of EAT. Subsequent experiments pointed to the relative contribution of both L3T4+ and Lyt-2+ cells, depending on the stage and extent of disease development. Treatment during disease with L3T4, but not Lyt-2, mAb alone significantly reduced thyroiditis. However, in situ analysis of the cellular infiltrate in thyroid sections revealed that, after treatment with mAb, the appropriate subset was eliminated without altering the amount of the other subset in the remaining lesion. In addition, treatment during severe thyroiditis following the transfer of MTg-activated lymph node cells showed that Lyt-2 mAb alone also reduced thyroid infiltration. When the recipients were pretreated with either pair of mAb before transfer, disease development was only moderately affected. We conclude that (i) donor L3T4+ cells are the primary cells responsible for the initial transfer and development of thyroiditis; and (ii) previous in vitro cytotoxicity data, plus current monoclonal antibody treatment of disease and in situ analysis, further implicate a role for Lyt-2+ cells in EAT pathogenesis.

Animals↗
PubMed1989

Pathogenic mechanisms in murine autoimmune thyroiditis: short- and long-term effects of in vivo depletion of CD4+ and CD8+ cells.

Both murine CD4+ and CD8+ cells are found in the thyroid infiltrate in experimental autoimmune thyroiditis (EAT) induced with mouse thyroglobulin (MTg). MTg activation of immune cells in vitro enables CD4+ cells to transfer thyroiditis adoptively and to aid the cytotoxic capacity of CD8+ cells for thyroid monolayers. To dissect their relative contribution to pathogenesis in vivo, depleting doses of paired rat monoclonal antibodies (MoAb) recognizing two distinct CD4 or CD8 epitopes were injected alone or in combination. Early treatment with CD4 MoAb interfered with the induction and development of EAT, whereas similar treatment with CD8 MoAb reduced infiltration moderately and did not enhance antibody response. To examine the long-term effect of therapy on advancing EAT, administration of MoAb was delayed to days 21 and 25, and thyroids were analysed immunohistochemically on days 28 and 70. Whereas control mice showed about 30% CD4+ and CD8+ cells at a 2:1 ratio (the remainder being mostly macrophages) on both days 28 and 70, the CD4 therapy regime led to reduced severity and the lesions on day 70 contained very low percentage of CD4+ cells, but elevated percentage of CD8+ cells (ratio 1:3.5). The CD8 therapy regime led to reduced CD8+ cells without changing the range of CD4+ cells (ratio 4:1). Thus, subset involvement may be influenced by the MoAb used. When CD4 and CD8 MoAb were combined, greater than 50% of the thyroids were cleared of all inflammatory cells; lesions when found were very small and contained less than 10% T cells (ratio 1:1). Since emerging T cells were not retained in the thyroid despite ongoing antigenic stimulus leading to increased antibody titres, the therapeutic effect of MoAb, even at an advanced stage of disease, was long lasting.

Animals↗
PubMed1989

A role for CD4+ but not CD8+ T cells in immunity to Schistosoma mansoni induced by 20 krad-irradiated and Ro 11-3128-terminated infections.

The role of CD4+ (L3/T4+) and CD8+ (Lyt-2+) T cells in immunity to Schistosoma mansoni induced by 20 krad-irradiated and Ro 11-terminated infections in mice was investigated directly by in vivo depletion of these subsets with cytotoxic rat monoclonal antibodies (mAb). Effective physical depletion was demonstrated by flow cytometric analysis and immunohistochemical staining. Functional depletion of helper activity following anti-CD4 treatment was indicated by an abrogation of concanavalin A(Con A)-induced colony-stimulating factor (CSF) release, while anti-CD8 treatment had no effect in these assays. Pre-existing S. mansoni-specific antibody levels were unaffected by anti-CD4 and anti-CD8 treatment. In vivo depletion of CD4+ T cells resulted in a dramatic reduction in immunity induced by one (up to 100%) and two (up to 70%) vaccinations with 20 krad-irradiated cercariae and also of resistance induced by Ro 11-attenuated infections (up to 100%). Depletion of CD8+ T cells had no effect on resistance induced by any of the vaccination protocols investigated. A correlation was observed between resistance and T cell-induced, macrophage-mediated killing of schistosomula in vitro, both of which were abrogated following anti-CD4 treatment but were unaffected by CD8+ T-cell depletion. The possible role of CD4+ T cells in vivo and the implications for vaccine development are discussed.

Animals↗
PubMed1989

Effect of CD4 monoclonal antibody in vivo on lesion development, delayed-type hypersensitivity and interleukin 3 production in experimental murine cutaneous leishmaniasis.

Highly susceptible BALB/c mice subjected to adult thymectomy followed by prolonged (15 weeks), twice-weekly injections of a low dose (100 micrograms) of CD4 monoclonal antibody (MoAb) develop resistance to otherwise uniformly fatal and disseminating Leishmania major infection. In contrast, similar treatment with CD8 MoAb has no effect on the course of L. major infection. CD4 MoAb administered after the lesion establishment also has no effect. Mice which become resistant following CD4 MoAb treatment developed the classical delayed-type hypersensitivity (DTH) which persisted at 72 h after footpad injection with killed L. major promastigotes. A substantial degree of resistance can also be induced in the BALB/c mice with two i.v. high doses of 500 micrograms of CD4 MoAb given immediately prior to L. major infection. The treated mice developed classical DTH and significantly smaller lesions. The spleen cells from these mice also produced significantly lower levels of IL-3 compared to that of untreated control mice when cultured with L. major antigens in vitro. In contrast, genetically resistant CBA mice treated with CD4 MoAb developed significantly larger lesions but lower levels of classical DTH compared to untreated mice. These data confirmed and extended earlier reports on the prophylactic effect of CD4 MoAb in susceptible BALB/c mice and the disease exacerbative effect in the resistant CBA mice. The data also further illustrate the direct correlation between classical DTH and resistance, and the inverse correlation between IL-3 production and resistance in experimental cutaneous leishmaniasis.

Animals↗
PubMed1988

T cell depletion with CAMPATH-1 in allogeneic bone marrow transplantation.

A total of 282 patients with leukemia have been treated by transplantation from HLA-matched siblings using marrow depleted of T cells with CAMPATH-1 and autologous complement. The incidence of graft-versus-host disease (GVHD) of grades 2-4 was only 12% but the maximum incidence of graft failure was 15%. A significant increase in relapse cannot yet be detected in acute leukemia but relapse in chronic granulocytic leukemia (CGL) was substantially above that reported before T cell depletion. The most important predictive factor for relapse in CGL appeared to be slow engraftment. This finding suggests an alternative explanation for the graft-versus-leukemia effect other than a direct attack on leukemia cells. This is that donor T cells may affect the balance of competition between donor and recipient haemopoesis by preventing a rejection reaction to donor stem cells. Recipient leukemic cells would benefit (i.e. relapse) if recipient hemopoiesis gained an advantage. If this explanation were true we would expect extra immunosuppressive preconditioning of recipients to reduce the incidence of relapse, as well as preventing graft rejection.

Acute Disease↗