Novel strategy to help prevent transplant rejection

Writing in the Journal of Clinical Investigation today, researchers from the University of Cambridge, the University of Edinburgh, Lorantis Ltd and Imperial demonstrate that it is possible in mice to alter whether T white blood cells specialise to attack foreign tissue and thus cause rejection, or instead become part of the body's peacekeeping force, which patrols the body, defending against attack.

Unlike current therapies, which leave patients vulnerable to infection by inducing non-specific immunosuppression, this new approach targets a key cellular signal known as Notch, which the researchers found acts as a gatekeeper by governing how immune cells specialise.

Results show that exposing the mice to a combination of the Notch signal and material from the donor two weeks in advance of transplantation stimulates an immune response and significantly increases transplant acceptance from 20 to up to 80 days.

Professor Maggie Dallman of Imperial's Centre for Molecular Microbiology and Infection, and senior author of the paper, said:

"Today, even with extensive efforts to find the best possible immunological match between donor and recipient, organ transplantation resigns the recipient to a lifetime of powerful immunosuppressive drugs that have many unwanted side effects.

"Increasingly organ transplants in the case of kidneys, liver or lung tissue occur between living relatives so you know in advance who the donor and recipient are. Our strategy opens up the possibility of offering gentler postoperative therapy by redirecting the recipient's immune system in advance of the transplant."

T cells are the arm of the immune system that patrol the body, seeking out and destroying diseased cells. There are two key types of T cells: T helper cells, which stimulate immune response, and T suppressor cells that put the brakes on it.

To test Notch's role in organ rejection the researchers transplanted a heart into the abdomen of a mouse. The heart was connected by two major vessels to the recipients blood supply so it had a beat but did not pump blood round the body.

When the mice were exposed to the pre-treatment regime, the length of time the heart was accepted for increased by up to four fold. This effect was found to be specific to pre-exposure to the foreign tissue that was subsequently transplanted and dependent on the presence of T suppressor cells at the time of transplantation.

"Results indicate that the presence of the Notch signal appears to promote the expansion of T suppressor cells, and provoke a corresponding decrease in T helper cells," says Professor Dallman.

"The key role that T suppressor cells play in preventing organ rejection is also supported by the observation that depleting their numbers at the time of transplantation reverses the effects of pre-treatment, and reducing the number of T helper cell numbers enhance transplant survival."

Further investigation indicates the mice did eventually reject the hearts because the T suppressor cells induced in these experiments only prevented one method of rejection.

"Rejection can occur by two mechanisms," explains Professor Dallman. "Either directly, where immune cells recognise transplant tissue as foreign, or indirectly through communication with other immune cells. The approach we used only targeted the direct method of rejection, but we believe that our approach will be equally effective against the indirect route when appropriately applied."

Professor Dallman added: "While the crucial role that Notch signalling plays in development has been well documented, scientists are only just beginning to examine its role in regulating the immune system.

"Now, we have an understanding of the key differences Notch signalling can impose on T-cell dependent immunity and, we believe that our approach may also be effective in the treatment of autoimmune diseases like diabetes or MS and in the treatment of allergy."

The clinical and commercial rights to this broad new approach to changing immune responses have been assigned to Lorantis Ltd. The company recently announced that it has raised £25 million from private equity venture funds to develop products based on Notch signalling in transplantation, autoimmune disease and allergy.

Dr Mark Bodmer, Chief Executive Officer of Lorantis Ltd, comments:

"The ability to selectively suppress the immune response to disease-causing antigens has the potential for immunotherapy by 'reverse' vaccination, where we down-regulate an unwanted response to an antigen rather than stimulate it. This represents a huge opportunity to benefit patients and build our company. We have been extremely pleased to be able to get strong financial support to move this important academic innovation into industry."

This work was funded by Lorantis Ltd, the European Union, the Wellcome Trust, the Medical Research Council and the British Heart Foundation.

-Ends-

For further information, please contact:

Judith H Moore
Imperial College London Press Office
Tel: +44 (0)20 7594 6702
Mobile: +44 (0)7803 886 248
E-mail:j.h.moore@imperial.ac.uk

Title: 'Notch ligation by Delta1 inhibits peripheral immune responses to transplantation antigens by a CD8+ cell-dependent mechanism'

J. Clin. Invest. 2003 112: 1741-1750.

Authors: Kenneth K Wong (1), Matthew J Carpenter (1), Lesley L Young (2), Susan J Walker (1), Grahame McKenzie (2), Alyson J Rust (2), George Ward (2), Laura Packwood (1), Karen Wahl (3), Luc Delriviere (4), Gerard Hoynes (3), Paul Gibbs (4), Brian R Champion (2), Jonathan R Lamb (3) and Margaret Dallman (1).

(1) Department of Biological Sciences, Imperial College London, UK

(2) Lorantis Ltd, Cambridge, UK

(3) Immunobiology Group, Respiratory Medicine Unit, Medical Research Council Centre for Inflammation Research, University of Edinburgh Medical School, Edinburgh, UK

(4) Department of Surgery, Addensbrooks Hospital, University of Cambridge, UK

Message posted by: Frank S. Zollmann