The overall aim of the project is to make clinical xenotransplantations possible. We shall concentrate on pigs as organ donors, although we will screen for possible other species as well. The project shall focus on carbohydrate related phenomena in xenotransplantation. In pig to man transplantation, hyperacute rejection occurs mainly as the result of reaction between carbohydrate antigens expressed on endothelial cells of the pig organ, and preformed anticarbohydrate antibodies of the recipient. A major target of these human natural antibodies is the nonreducing terminal disaccharide Gal alpha,3Ga We shall focus on strategies to inhibit/interfere with carbohydrate dependent rejections in xenotransplantation. The studies proposed will partly take place in close collaboration with industry.
Part of the technology for the production of final products (Columns, etc) is known from other areas, indicating a possible market within 3-5 years. Additional basic knowledge will be produced that will contribute to the production of a new generation of anti-inflammatory/anti-rejection drugs. The market for carbohydrate products in relation to xenotransplantation was recently, perhaps optimistically, estimated to I billion dollars in a "full scale" scenario.
Our present view is that the disarming of only one of the several pathogenic routes will be insufficient to ensure success. The binding of anticarbohydrate antibodies is followed by complement activation and cell mediated events at later stages. All these different rejection events require specific approaches for their prevention. In that perspective we will also combine a number of different strategies for prevention of xenograft rejection. We envisage to use pig organs that are transgenic for human complement regulatory proteins or apply other methods to block complement activation. In addition, we think of strategies to block leucocyte influx into the tissue.
Transplantation as a medical treatment that has been extremely successful during recent years. 5 year graft survival for kidney allografts is about 80% using nonrelated human donors and about 90 % using related donors. Transplantation of an organ to a seriously ill patient in most cases results in a full quality life. At present, the shortage of donor organs, is the only hindrance for curing thousands of patients in Europe. Compared to conventional therapy, if existing, transplantation is a relatively non-expensive treatment. The economic benefit for the national health care budgets is substantial taking into account the decreased need for continuous treatment, and treatment of related complications and also the fact the many/most transplanted patients regain an active professional life.
The project proposed is transdiciplinary, ranging from basic molecular biology/cell biology/structural biology over clinical trials to ethical and cultural aspects. It is problem-oriented from its start, it contains important basic research as well as more applied research and still the participant researchers are all well founded in their own disciplines. Such a project will speed up the solution to an important medical problem with impact on health care and society and it will also promote cross fertilization and the development of novel concepts worthy of further basic diciplinary research.
More specifically we will:
- develop, produce and test carbohydrate based inhibitors/immunoadsorbents for clinical use.
- test and evaluate the use of glycosylhydrolases and blocking antibodies to abolish or cover antigen expression.
- develop animal and human models to test the different therapeutic concepts. - try to understand the regulation of "terminal" glycosyltransferases with the purpose of creating low expressors of Galal ,3Gal.
- screen for additional carbohydrate related rejection phenomena - produce a documentary TV-film on xenotransplantation from a cultural, historical and ethical perspective and a scientific report on ethical attitudes in relation to ethical structures and norms.
Funding SchemeCSC - Cost-sharing contracts
141 86 Huddinge
2300 RC Leiden
1081 BT Amsterdam