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S Cobbold

Publications and source records attributed to S Cobbold.

At least 19 recordsLinked to original sources
PubMed1999

CD4 T cells can reject major histocompatibility complex class I-incompatible skin grafts.

We have re-investigated the roles of CD4 and CD8 T cell subsets in skin graft rejection across a single class I MHC disparity. Recipient mice were transplanted with skin from donors transgenic for the class I MHC molecule Kb. As expected, CD8 T cells were sufficient for rapid injection; but surprisingly, CD4 T cells were also competent to do the same. Rejection was dependent on one or the other subset, since elimination of both resulted in indefinite graft survival. The possibility that alloantibody was the downstream effector of CD4 mediated rejection was excluded because CD8-depleted mice rendered B cell deficient still rejected rapidly, but T cell-depleted recipients with pre-existing high titers of alloantibody were unable to do so. In addition, if CD4 cells act to reject by recruiting and/or activating macrophages then this was not dependent on CR3, IFN-gamma or TNF-alpha. Transplantation of skin grafts where the MHC class I disparity was at the level of passenger leukocytes only, demonstrated that transient bystander damage could occur, but that this was insufficient to result in full rejection. We surmise that for CD4 T cells to reject an MHC class I-incompatible graft it is necessary that an appropriate allogeneic peptide is processed and presented in the context of recipient MHC class II. CD4 T cells from B6 mice may fail to reject skin from MHC class I mutants because of the lack of such MHC class II-restricted presentation.

Animals↗
PubMed1998

Mechanisms of protection induced by attenuated simian immunodeficiency virus. II. Lymphocyte depletion does not abrogate protection.

To determine the role that cellular immune responses play in the protection conferred by vaccination with attenuated SIVmac32H (pC8), we have attempted to deplete macaques of their CD8+ cells prior to challenge with wild-type SIVmac32H (pJ5). In two of four pC8-infected macaques, N109 and N112, a transient partial depletion of CD8+ cells by antibody treatment was achieved. On the day of challenge peripheral CD2+CD4-CD8+ cell counts were reduced by 92 and 95%, respectively, in animals N109 and N112 and their lymph nodes revealed a 46 and 58% reduction, respectively, in CD2+CD4-CD8+ cells. Two other pC8-immunized macaques, N110 and N111, treated in the same way, did not show significant depletion of CD8+ cells. None of these four pC8-immunized animals became infected when challenged with 50 MID50 of pJ5. Treatment of a further four pC8-infected and protected macaques and two naive control animals with Campath-1H antibody successfully depleted peripheral CD3+ cell counts by >99% in all treated animals. Campath-1H depletion resulted in enhanced, longer lasting lymphoid depletion. Yet subsequent challenge with 20 MID50 of pJ5 still failed to infect the pC8-immunized animals. All eight of the naive controls, including two Campath-1H-treated animals, became infected following challenge. In summary, partial depletion of circulating CD8+ cells or total lymphocytes prior to challenge failed to abrogate the protection conferred by vaccination with pC8.

Animals↗
PubMed1998

Bone marrow transplantation induces either clonal deletion or infectious tolerance depending on the dose.

The concept of immunologic tolerance arose from bone marrow transplantation in neonatal or irradiated mice, in which the predominant mechanism is clonal deletion of donor-specific T cells by donor hemopoietic cells in the recipient thymus. A short term treatment with nonlytic CD4 and CD8 mAbs can induce tolerance to tissue allografts or reversal of spontaneous autoimmunity. Such tolerance to skin or heart allografts is dependent on "infectious" tolerance mediated by regulatory CD4+ T cells. We show here, for multiple minor Ag differences, that while a large inoculum of donor marrow produces significant deletion of Ag-reactive cells as expected, a low marrow dose generates tolerance with little evidence of clonal deletion. Only this low dose tolerance can be transferred to unmanipulated recipients via CD4+ T cells, can be passed onto naive T cells as if infectious, and can act to suppress rejection of third party Ags when "linked" on F1 grafts.

Animals↗
PubMed1998

Tolerance induction with CD4 monoclonal antibodies.

One of the major goals of therapeutic immunosuppression is to be able to use short-term therapy to achieve long-term tolerance. Short courses of CD4 antibodies are able to create peripheral tolerance in a mature immune system. The resulting tolerant state shows evidence of being dominant in that one can observe the features of linked suppression, transferable suppression and infectious tolerance in a variety of model systems. Only in the situation of administration of high doses of marrow could one find evidence of central and peripheral tolerance which had all the features of being deletional rather than regulatory. These findings suggest that attaining dominant tolerance and linked suppression may be the least invasive of all tolerance-inducing strategies for clinical application.

Antibodies, Monoclonal↗
PubMed1998

Infectious tolerance.

Infectious tolerance can be induced in many ways, does not require a thymus or clonal deletion and can spread to third-party antigens linked on the same antigen-presenting cell-the process being variously described as linked-, bystanderor epitope-suppression. We here review the evidence concerning the mechanisms involved and attempt to make a consistent hypothesis, that during tolerance induction in the Th1-mediated autoimmune diseases and transplantation systems there would seem to be a phase of immune deviation towards Th2 cytokines, like IL-4 and IL-10; however, this may lead to an IL-10-induced form of anergy or nonresponsiveness and generation of the recently characterized Th3/T-regulatory-1 CD4+ T cell subset which is thought to downregulate the antigen-presenting cell, possibly via transforming growth factor beta.

Animals↗
PubMed1998

How do monoclonal antibodies induce tolerance? A role for infectious tolerance?

One of the major goals in therapeutic immunosuppression has been to achieve long-term benefit from short-term therapy. The discovery in the mild-1980s that CD4 antibodies can induce immunological tolerance without depleting CD4+ T cells has reawakened interest in the use of nondepleting monoclonal antibodies for reprogramming the immune system in autoimmunity and in transplantation. Since that time, antibodies to CD11a, CD4OL, CD25, CD3, and CTLA4-Ig have all been shown capable of facilitating tolerance. In order to apply to principle of reprogramming in the clinic, we have sought to understand the mechanisms that are involved in its induction and its maintenance. In a number of allogeneic transplant models (heart, skin, bone marrow) anti-CD4 (+/- CD8) antibodies can be shown to block the rejection process while selectively promoting the development of CD4+ regulatory T cells responsible for a dominant tolerance that is reflected in findings of linked suppression and infectious tolerance. In these models, T cells that have never been exposed to CD4 antibodies become tolerant to grafted antigens by experiencing antigen in the microenvironment of regulatory T cells. Dominant tolerance is not the only mechanism that can be facilitated by CD4 Mab therapy. If allogeneic marrow is given at high cell doses under the umbrella of CD4 and CD8 antibodies, then tolerance can be achieved through clonal deletion. The mechanism by which regulatory CD4+ T cell suppress is not yet defined but could be active or passive. We have proposed the "civil service model" to explain how tolerant T cells might interfere with the responses of competent T cells in such a way as to render them tolerant.

Animals↗
PubMed1994

Mechanisms in CD4 antibody-mediated transplantation tolerance: kinetics of induction, antigen dependency and role of regulatory T cells.

CBA/Ca mice may be made tolerant to minor histoincompatible B10.BR skin grafts by treatment with a short course of non-depleting anti-mouse CD4 and CD8 monoclonal antibodies (mAb), during the transplantation period. We wished to determine when, in relation to antibody therapy, the T cells became tolerant. This was investigated by a series of adoptive transfer experiments in which mAb-treated cells were removed from therapeutic antibody at defined times after skin grafting, and exposed to fresh antigen in the absence of further mAb treatment. We show here that T cells do not become fully tolerant until 5 weeks after skin grafting. If antibody therapy is continued for the full 5 weeks, T cell tolerance can still be established, suggesting that antibody therapy does not prevent lymphocytes from registering the presence of antigen. Once the tolerant state is established, it is difficult to break that tolerance by lymphocyte infusions from normal donors. This "resistance" is mediated by T cells of the tolerant host. We show that the maintenance of both tolerance and "resistance" requires a continuous supply of antigen. When tolerant cells were "parked" in T cell-depleted mice, tolerance and "resistance" were eventually lost by 6 months. In contrast, "parked" cells exposed to fresh antigen at any time up to 4 months remained tolerant and "resistant" indefinitely. Finally, we wished to establish whether "resistance" was peculiar to this form of peripheral tolerance, or whether it might also be present in tolerance considered to be classically central. We observed resistance to be greater in the mAb-treated peripherally tolerant group, but noted that some of the centrally tolerant animals also exhibited a level of resistance above that of T cell-ablated controls. This suggests that a tolerance mechanism whose role is only minor in central tolerance may have a major role in antibody-mediated peripheral tolerance.

Animals↗
PubMed1994

What can be done to prevent graft versus host disease?

Graft versus host disease presents a major obstacle to the widespread application of allogeneic bone marrow transplantation despite improvements in drug prophylaxis. Although animal models are providing an understanding of the biology of the process, opportunities for exploitation of that knowledge for therapeutic purposes are still limited. One way to overcome this impasse is to build on the positive benefits of T-cell purging of marrow, by combining it with intelligent correction of the known negative effects.

Animals↗
PubMed1994

Monoclonal antibodies that define canine homologues of human CD antigens: summary of the First International Canine Leukocyte Antigen Workshop (CLAW).

A panel of 127 monoclonal antibodies against canine leukocyte antigens, including controls, was distributed to 29 laboratories that performed a variety of experiments to identify groups of antibodies against the canine equivalents of some of the human CD antigens. Cluster analysis was performed centrally, using the submitted antibody binding data from immunofluorescence, ELISA and immuno-histology experiments. Immunoprecipitation for molecular weight determination was also performed centrally with T-cell blasts and a B-cell line as the sources of antigen. Clusters of three or more antibodies were found that defined the canine equivalents of the CD5, CD4, CD8 and Thy-1 antigens, and these could be used to label T-cell subsets from the peripheral blood. Other groups of monoclonal antibodies recognized the canine homologues of the CD11/18 group of antigens, CD44 and the CD45/CD45R antigen family: these should be useful in isolating functional subsets of CD4+ helper T cells. There was a cluster of four antibodies that bound strongly to platelets (probably CD41 antigen), three antibodies that were specific to B cells (including CD21) and two antibodies against a granulocyte antigen (possibly CD15). A number of reagents were found against canine MHC-II and immunoglobulin, with some of the latter able to distinguish between Ig subclasses. Properties of each of the canine antigens defined by these monoclonal antibodies are discussed and compared with other species. The availability of such a panel of reagents should allow rapid improvements in the immunological diagnosis of canine disease, and there might now be a potential for testing novel therapeutic strategies in a clinical veterinary setting.

Animals↗
PubMed1993

The use of monoclonal antibodies to achieve immunological tolerance.

Monoclonal antibodies are potentially useful immunosuppressive agents. Short course 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, reviewed by Herman Waldmann and Stephen Cobbold, 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

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↗