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HOW DO MONOCLONAL ANTIBODIES INDUCE TOLERANCE? A Role for Infectious Tolerance?

HOW DO MONOCLONAL ANTIBODIES INDUCE TOLERANCE? A Role for Infectious Tolerance? ▪ Abstract One of the major goals in therapeutic immunosuppression has been to achieve long-term benefit from short-term therapy. The discovery in the mid-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 the 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 cells 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. The application of dominant infectious tolerance and linked suppression to clinical immunosuppression should not be underestimated because it suggests that tolerance acquired (through therapy) to a limited set of antigens can spread to embrace all others in the tissues under attack. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Annual Review of Immunology Annual Reviews

HOW DO MONOCLONAL ANTIBODIES INDUCE TOLERANCE? A Role for Infectious Tolerance?

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Publisher
Annual Reviews
Copyright
Copyright © 1998 by Annual Reviews. All rights reserved
Subject
Review Articles
ISSN
0732-0582
eISSN
1545-3278
DOI
10.1146/annurev.immunol.16.1.619
pmid
9597144
Publisher site
See Article on Publisher Site

Abstract

▪ Abstract One of the major goals in therapeutic immunosuppression has been to achieve long-term benefit from short-term therapy. The discovery in the mid-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 the 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 cells 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. The application of dominant infectious tolerance and linked suppression to clinical immunosuppression should not be underestimated because it suggests that tolerance acquired (through therapy) to a limited set of antigens can spread to embrace all others in the tissues under attack.

Journal

Annual Review of Immunology – Annual Reviews

Published: Apr 1, 1998

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