Stem cells are multipotent cells of the immune system. Scientists hope to use them for curing autoimmune diseases, cancer and innate genetic defects in the future. What is possible today, which barriers still need to be overcome and how research in this area is progressing - these were topics of the lecture held by Professor Fritz Melchers, a doyen of immunology and Honorary President of the 2nd European Congress of Immunology in Berlin at a Press Conference.
For decades now, experimental and clinical immunology has been using cell transplants for multiplying and restoring the hematopoietic (blood-forming) system of our body, i.e., of red blood cells and cells of the innate and the adaptive immune system. A clinically successful cell therapy which is performed more than 30,000 times a year is bone marrow transplantation. It is particularly widely applied in cancer patients for life-long restoration of the deathly damaged hematopoietic system after chemotherapy or radiotherapy.
Severely immunodeficient children also receive bone marrow transplants to repair their defective system using bone marrow cells of a suitable healthy donor. This is possible because the bone marrow contains small amounts of what are called hematopoietic stem cells. It has been shown experimentally that, in principle, a single stem cell is capable of restoring the whole system of over 2000 billion blood and immune cells.
A serious problem of such transplantations continues to be what is called tissue incompatibility. This means that the recipient's (patient's) immune system - even in the deficient state that is sometimes left in cancer patients and immunodeficient children - rejects and destroys the cells of the donor, i.e., the stem cells and the blood and immune cells derived from them. In the reverse case, it can also happen that the donor cells attack the patient's organism. In clinical transplantation practice, these rejections are suppressed by chemical substances, i.e., immunosuppressive drugs that have to be taken life-long after transplantation. Immunosuppressants naturally weaken the defense of the newly restored immune system against infections and affect the control of autoimmune (directed against the own body) reactions of the system.
"Thus, we are searching for tissue-compatible forms of transplantation. It would be best if the cancer patient could receive his or her own healthy stem cells, because they would be tolerated and not rejected," says Melchers. "However, since the bone marrow of cancer patients is 'contaminated' by cancer cells, transplantation of 'own' bone marrow is out of the question."
In severely immunodeficient children, the stem cells are defective, too. In the past, Professor Alain Fischer of the Hôpital Necker in Paris tried to correct the deficient stem cells of these children by repairing the defective gene and subsequently returning the gene-therapeutically repaired stem cells to the immunodeficient children. This was successful in approximately ten cases. However, some of the transplanted children developed blood tumors as a result of the mutagenic effect of the retroviral gene delivery vehicle. Retroviruses are used as "gene ferries" to insert the repaired gene into the genome of the stem cells. Although the tumors could be cured, the severe immunodeficiency remained.
The lack of success of this gene therapy has been attributed to the fact that retroviruses insert the repaired genes at random places in the stem cell genome where they can act as mutagens and, thus, cause cancer. Therefore, an intact copy of the defective gene should be inserted into the genome at the exact place of the genetic defect and should thereby replace the defective gene. However, this process called homologous recombination is possible only in a single type of cells, embryonic stem (ES) cells.
What are ES cells? They are formed once, three and a half days after fertilization of the egg cell, as 64 blastocysts. For some time now, it has been possible to multiply these blastocysts as ES cell lines in tissue culture and to replace specific genes in the genome by homologous recombination in a targeted approach. Thus, it would also be possible to repair the defective gene of an immunodeficient child without running the risk of causing cancer. But, unfortunately, the ES cells of the child have long since disappeared, because the whole organism has developed from them.
The tissue culture methods developed two years ago primarily in the laboratories of Yamanaka in Kyoto and Jaenisch in Boston have made it possible, for the first time, to develop such ES cells, cautiously called "induced pluripotent stem cells" (iPS cells) by Yamanaka, from differentiated body cells such as skin cells. Thus, scientists will probably soon be able to derive iPS cells from skin cells of an immunodeficient child and to repair the child's genetic defect by replacing the defective form of the gene with a functioning, normal one by homologous recombination. We can also expect that it will be possible to produce a cancer patient's "own" individual, tissue-compatible iPS cells from his or her cancer-free skin cells. Using recently developed tissue culture methods, it is possible to subsequently generate hematopoietic stem cells from these repaired iPS cells. The former can then be transplanted into the child or cancer patient to repair their hematopoietic systems.
It will certainly take another few years for this method of bone marrow transplantation, which is principally feasible now, to be implemented in clinical practice for repairing immune deficiencies in children. But the experimental groundwork has already been done.