Research Finds Effective Stem Cell Applications in Immune and Organ Function

While the debate over the ethical implications of stem cell research continues to embroil medical and political communities, researchers are successfully demonstrating the therapeutic value of human stem cells in a wide variety of diseases.

Threestudies being presented today at the 48th Annual Meeting of the American Society of Hematology (ASH) suggest that the use of stem cells mayimprove the treatment of life-threatening diseases while simultaneouslydecreasing complications from therapy.

"We know that stem cells may be the key to developing more effectiveand less toxic therapies to fight a host of diseases in the future," says Stephen Emerson, MD, PhD, of the University of Pennsylvania, Philadelphia. "While we are working together to determine the best way to extract thesecells without causing any human harm, continued research -- like the studies presented here -- offers a significant benefit by identifying themany possible applications of this therapy."

Several of the studies being presented review stem cell therapy inrelation to the transplantation process, which can result in a variety ofcomplications based on the donor's relation to the recipient. The outcomesof related and unrelated donor cell transplants depend heavily on thedegree of human leukocyte antigen (HLA) matching between the transplantrecipient and the donor.

Matching HLA is extremely important to successfulengraftment, frequency and severity of graft-versus-host disease (GVHD),and overall survival post-transplant. A haploidentical transplant usescells from a relative who is not HLA-matched but who has common relatedgenes with the recipient, including parents and sometimes siblings. For patients with an urgent transplant need and without identical HLA-matchedrelatives, a haploidentical match is often the next best option.

Mesenchymal Stem Cells for Treatment of Severe Acute Graft-Versus-Host Disease

Research in stem cell therapy has expanded to a variety of diseases asresearchers discover the value of human stem cells in treating illnesses like cancer and heart disease. In this study, a team of researchers from Sweden examined the value of stem cell therapy for severe graft-versus-hostdisease (GVHD), a major complication of blood transplants that replace damaged cells due to leukemia and other disorders. During successful transplants, the donated cells engraft or implant within the patient's bone marrow, where they grow and provide a new source of blood and immune cells.GVHD occurs when T- cells from the donor (the graft) respond to the hostcells in the patient's body as foreign and attack them.

A total of 40 patients with severe (grades III-IV) acute GVHD weregiven varying doses of therapy with mesenchymal stem cells (MSC), derivedfrom bone marrow: one dose (19 patients), two doses (19 patients), threedoses (2 patients), or five doses (2 patients). The stem cells were donatedfrom HLA- identical sibling donors (5), haploidentical donors (19), andHLA-mismatched donors (41).

The results of the trial therapy were successful overall, as 19 patients experienced a complete response and nine additional patientsshowed some improvement. The disease stabilized in four patients but did not improve. In seven patients the treatment did not provoke a response,and one patient was not evaluated due to short-term participation. No side effects were seen after the MSC infusions. The team has continued to followup with patients (up to 3.5 years); of the 21 surviving patients, nine havechronic GVHD, one patient has recurrent leukemia, and one has de novo AML.

"Based on the results of this study, we are optimistic that mesenchymalstem cells do in fact have measurable value in repairing human tissues,"says Katarina LeBlanc, MD, PhD, of the Karolinska University Hospital Huddinge, Stockholm, Sweden, and lead author of the study. "This therapyshould be further explored in randomized trials as an effective and safeway to treat severe acute GVHD."

Offering explanation for the possible value of MSCs in treating GVHD,researchers noted that MSCs derived from adult bone marrow have thecapacity to differentiate into several types of mesenchymal tissue and areproven to inhibit T-cell alloreactivity in vitro. Therefore, the disease characteristic of attacking the host body's cells is blocked by the injection of these stem cells.

Long-Term Safety and Efficacy of Stem Cell Gene Therapy for ADA-SCID

Severe combined immunodeficiency (SCID) is caused by a severe genetic defect often found in newborns. Because the immune system is so severely compromised, exposure to even benign germs can result in serious or life-threatening infections like pneumonia, meningitis, or bloodstreaminfections. The condition must be diagnosed and treated quickly to prevent serious complications, and doctors continue to struggle with often ineffective treatment options. In this study, a team of Italian researchersfound that the use of stem cells may effectively fight SCID caused by adeficiency of the ADA gene (adenosine deaminase), which is critical for the immune system to function properly.

Previous research has shown that immune function has improved whenpatients were given an autologous hematopoietic stem cell transplant (HSC),from the body's own bone marrow, combined with the ADA gene. The currentphase I/II study treated eight ADA-SCID children (ages 7-67 months) withHSC conditioned with busulfan, a treatment that helps with the engraftment process. After following patients for an average of three years, researchers have seen no adverse events related to the gene transfer. Infact, they have observed that the stem cells have successfully integrated into the patients' marrow, giving rise to genetically repaired blood cells.

In the six children with a follow-up of more than one year, white blood cell counts progressively increased and T-cell functions normalized. Inaddition, tests found the presence of antigen-specific antibodies (proteinsthat help the immune system identify and fight bacteria and viruses). Infive patients, levels were high enough to discontinue supplemental antibody treatment.

"We feel that these data confirm the safety and efficacy of genetherapy in improving immune and metabolic function in children diagnosedwith this form of severe combined immunodeficiency," says Alessandro Aiuti, MD, of the San Raffaele Telethon Institute for Gene Therapy in Italy and lead author of the study with Maria Grazia Roncarolo, MD. "This may represent a viable solution to reduce the mortality rates associated with SCID in newborns."

At the conclusion of the study, all participants were healthy, with no severe infections, up to six years from the treatment. Researchers noted that because the ADA genes had sustained activity in the blood cells, the children's growth and development has continued to improve.

The treatment is funded by the Italian non-profit Telethon Foundation,a major charity that raises and distributes funds in Italy for biomedicalresearch on genetic diseases, and has recently attained Orphan Drug statusfrom the European Medicines Agency (EMEA).

Cord Blood Mesenchymal Stem Cells for Acute Renal Failure Repair

As scientists continue to discover new applications for human stem cells, they are targeting diseases with a significant need for more efficacious treatment options. Until recently, pharmacologic therapies foracute renal failure have been generally unsuccessful, so the potential therapeutic value of mesenchymal stem cells (MSCs) is particularly intriguing.

In this study, a team of researchers in Italy obtained MSCs from full-term umbilical cord blood to test their therapeutic value on renal tissue in mice with acute renal failure. The team successfully isolated MSCs from approximately 18 percent of the processed cord blood units, confirming the rate obtained by other stem cell studies. Testing of the MSCs also confirmed certain characteristics that help induce tissue repair,like the development of bone and cartilage.

Ten immunocompromised mice with acute renal failure received either cord blood MSCs or intravenous saline (control) and were evaluated for renal function and histology. Renal tissue was evaluated at day four andassigned a score (0-3) measuring the level of damage.

The MSCs significantly protected the mice from renal functionimpairment at day four, which was noted by reduced levels of blood ureanitrogen (a waste byproduct caused by kidney malfunction) from 115 mg/dl(saline) to 64 mg/dl (MSCs). Tissue damage was also reduced in the stem cell-treated mice (score of 0.5) compared to saline-treated mice (score of1.0) as demonstrated by Marina Morigi, PhD, of Mario Negri Institute of Pharmacological Research in Bergamo, Italy, who conducted the in vivostudy.

"These preliminary results indicate that human mesenchymal stem cells do exhibit reparative potential in acute renal failure," says LorenzaLazzari, PhD, of the Cell Factory, Department of Regenerative Medicine at Fondazione Policlinico in Milano, Italy, and lead author of the study. "With more evidence demonstrating their value in human subjects, the unique therapy of human stem cells may offer patients with renal failure a safer and more effective way to combat the illness."

This study was sponsored by European Community.