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Stem cells – tailor-made transplants

New methods of cell selection make it possible: even parents or siblings with non-identical tissue features can donate blood stem cells in order to help children with leukaemia, for example.

About two thirds of children with leukaemia have the good fortune to have a suitable sibling or outside donor who can supply stem cells to regenerate their immune system. The University Clinic for Paediatrics and Youth Medicine in Tübingen under the direction of Dr. Rupert Handgretinger offers an alternative to the remaining third: haploidentical stem cell transplantation.

Stem cell development into all kinds of different cells. (Figure: University Clinic for Paediatrics and Youth Medicine, Tübingen)

Stem cell development into all kinds of different cells. (Figure: University Clinic for Paediatrics and Youth Medicine, Tübingen)

With conventional procedures, parents are not suitable as donors because the child inherits tissue features (HLA alleles) from both parents - half from each. So half of the parental features do not fit; the parents are haploidentical. Donor cells with non-identical features can cause life-threatening graft rejections. It has been possible for some years to remove the incompatible cells from the transplant using special methods of cell separation. Handgretinger and his team have refined this method and brought it a crucial step forward.

Parents can only "half-fit"; they are haploidentical.

"We have been able to optimise haploidentical transplantation to the point where we don’t lose any patients to side effects. We have an almost zero mortality rate. This is enormous progress. Now we are concentrating on preventing relapses," says the hospital director. An extremely fruitful cooperation is jointly responsible for this positive development: Handgretinger is working closely with Miltenyi Biotech, a company that manufactures magnetic microbeads to customer specifications.

Magnet-activated cell sorting (Figure: University Clinic for Paediatrics and Youth Medicine, Tübingen)

Magnet-activated cell sorting (Figure: University Clinic for Paediatrics and Youth Medicine, Tübingen)

The microbeads are coated with antibodies that bind specifically to the surface molecules of certain blood cells. In the magnetic field, these cells are held back, subsequently eluted and used as a graft. Until recently, Tübingen and other international centres carried out CD34 antigen screens. CD34 is a transmembrane glycoprotein that is specifically expressed on progenitor cells. In the meantime, the Tübingen team changed from this positive enrichment to negative selection, which they themselves developed. With the substantially more effective CD3 and CD19-depletion, B and T cells (the cells that are responsible for the main complications in stem cell transplantation) are labelled and sorted out with microbeads.

The advantage of this: the otherwise unchanged blood can serve as a transplant. It also contains the therapeutically important natural killer cells (NK cells). "We try to put the immune effect of the new graft, or rather the anti-leukaemia effect of the NK cells, to better use. In this way we also want to prevent relapses more effectively," says Handgretinger..

Dual strategy

The experienced stem cell researcher is not only busy with haematopoietic stem cells. Handgretinger is also pursuing various projects in the field of mesenchymal stem cells and is working on co-transplantations, where mesenchymal stem cells are used together with haematopoietic stem cells. He hopes that this will lead to crucial progress in the treatment of metabolic diseases such as metachromatic leukodystrophy. With this disease, the patient suffers from a deficiency in arylsulfatase, which leads to damage of the white matter in the brain. This can cause various symptoms, ranging from coordination disturbances to paralysis and epileptic seizures.

"The advantage of mesenchymal stem cells is that they produce greater amounts of arylsulfatase. The advantage of the haematopoietic stem cells is that the enzyme-producing cells can also partially enter the brain," explains Handgretinger. He also sees co-transplantation potential in the treatment of osteogenesis imperfecta (one of the brittle bone diseases). In this disease, the osteoblasts are defective and no longer produce sufficient collagen. A co-transplantation could correct this effect if the stem cells were to transdifferentiate into osteoblasts in the local environment. Whether this will work or not is currently being investigated in vitroi in Tübingen.

Unfortunately, co-transplantations also entail some problems. "The regenerative effect fades after the first transplantation. This is probably connected to the lifespan of the mesenchymal stem cells. These probably do not have the necessary long-term pluripotentiality, while the haematopoietic stem cells totally exhibit a sufficient capacity for self-renewal," says Handgretinger. The Tübingen group wants to explain the exact connections with a humanized mouse model.

Stem cell transplantation has great therapeutic potential

Over the long-term, Handgretinger would like to implement his results in the field of organ transplantation. "After stem cell transplantation, a leukaemia patient could receive practically any organ transplant. We want to make the advantages of stem cell transplantation available to liver transplantation, for example. A combined organ and stem cell transplantation could prevent a child from needing long-term immunosuppression."

Stem cell production in the clean-room laboratory using the Clinimacs device (Figure: University Clinic for Paediatrics and Youth Medicine, Tübingen)

Stem cell production in the clean-room laboratory using the Clinimacs device (Figure: University Clinic for Paediatrics and Youth Medicine, Tübingen)

Handgretinger also sees application possibilities for transplantations of the intestines. If children are born without an intestine, parents could donate intestine and their immune system at the same time in order to prevent graft rejections. This is not yet feasible, but visionary researchers and physicians such as Handgretinger are the ones who will make such therapies possible one day - and not least because the environment is right. "In the field of paediatrics we rank both in Germany and internationally as a prominent centre for stem cell transplantation. We do the transplantation here in our hospital. We have authorization to manufacture, good GMP conditions and we work basically like a pharmaceutical company - except that our products are not medicines, but adult stem cells," says Handgretinger.

One day, hopefully in the not too distant future, haploidentical stem cell transplantations could be part of the physicians' repertoire of therapies for serious forms of autoimmune diseases such as rheumatoid arthritis, diabetes and scleroderma.

leh - 20.08.06
© BIOPRO Baden-Württemberg GmbH, originally published at www.bio-pro.de<, the Biotech/Life Sciences Portal of the State of Baden-Württemberg. All rights reserved.

Further information:

University Hospital of Tübingen
University Clinic of Paediatrics and Youth Medicine
General Paediatrics, Haematology, Oncology
Prof. Dr. med. Rupert Handgretinger (Medical Director)
Hoppe-Seyler-Str. 1
72076 Tübingen

Phone: +49 (0)7071 29-84744
Fax: +49 (0)7071 29-4713
rupert [dot] handgretinger [at] med [dot] uni-tuebingen [dot] de
www.medizin.uni-tuebingen.de<