HERMAN WALDMANN

A pharmaceutical comprising a therapeutic protein that binds to a therapeutic target, the protein being modified with a compound that inhibits binding of the protein to the therapeutic target, the modified protein being effective for reducing an immune response against the protein and for producing a therapeutic effect by binding to the therapeutic target. The therapeutic protein may be an antibody that includes an antibody combining site that binds to the therapeutic target.

The field of tissue transplantation has revolutionized the treatment of patients with failing organs. Its success, thus far, has depended on combinations of immunosuppressive drugs that damp host immunity, while also imposing numerous unwanted side‐effects. There is a longstanding recognition that better treatment outcomes, will come from replacing these drugs, fully or in part, by taking advantage of tractable physiological mechanisms of self‐tolerance. The past 50 years have seen many advances in the field of self‐tolerance, but perhaps, the most tractable of these has been the more recent discovery of a subset T‐cells (Treg) whose role is to regulate or damp immunity. This article is intended to first provide the reader with some historical background to explain why we have been slow to identify these cells, despite numerous clues to their existence, and also to indicate how little we know about how they …

The present invention provides for a novel method for inhibiting an undesirable immune response, especially in transplant recipients such as those having received an allo geneic stem cell transplant. Also disclosed are related com positions and kits for inducing immunotolerance.

In 1993 we published a paper entitled “Infectious Tolerance” in Science magazine [1]. We had used a short-term pulse of coreceptor-blocking antibodies to generate long-term acceptance of, and antigen-specific tolerance to, transplanted tissue in mice. The same term “infectious tolerance” had been used in a different way much earlier by Richard Gershon, to claim that T-cells could suppress immune responses as well as promoting them [2]. Perhaps, in retrospect, we should have chosen a different title such as “Contagious Tolerance” to better convey the point that, tolerance was being maintained by a sustained recruitment of regulatory T-cells. Importantly though, for this article, our own observations on T-cell mediated suppression and infectious tolerance were observed in lymphoreplete mice [1],[3],[4],[5],[6].In contrast, the “classical” demonstrations of natural regulatory T-cells (nTreg) came from adoptive studies …

We have previously demonstrated that short-term coreceptor blockade with non-lytic monoclonal antibodies enables the long-term survival of fully allogeneic embryonic stem cell (ESC) transplants in mice. Here, we describe the use of Hu-PBL humanized mice to determine whether short-term coreceptor blockade with humanized anti-human CD4 and CD8 antibodies can achieve the same outcome towards human ESC derivatives. While control Hu-PBL mice rejected allogeneic hESC-derived transplants within weeks, mice treated with coreceptor blocking antibodies held their grafts for 7 weeks, the duration of the study. Rejection in the control mice was associated with demonstrable infiltrates of human CD45 white blood cells, predominantly of CD8 T-cells, whereas anti-CD4, but not anti-CD8 antibody treated mice showed remarkably reduced lymphocyte infiltration and prolonged allograft survival, indicating that …