Interleukin-17A Augments Mesenchymal Stem Cell Function

One of the biggest problems with organ transplantations is that the immune system can reject the transplanted tissue. Transplant rejection requires the patient to go through another traumatic surgery, and if another organ is not available, then they might very well die. Is there a way to reduce organ rejection?

Our bodies have on our cell surfaces a series of “bar codes” that are the result of “Major Histocompatibility Antigens” or MHC proteins. These proteins are encoded by genes that vary extensively. Therefore, each person has a distinct combination of cell surface proteins that decorate the outside of their cells. If your immune system finds cells that have a different set of MHCs that what you were born with, the immune system, which has been “taught” to accept your own proteins and reject different proteins, will attack and destroy the transplanted tissue. This is known as “Graft vs Host disease” or GvHD. To avoid GvHD, transplant physicians try to find organs that match your own tissue type as closely as possible. However, it is virtually impossible to find organs that perfectly match your own. Even if the patient is given anti-rejection drugs, sometimes the immune system begins to reject the transplanted organ. Is there a way around this?

Mesenchymal stem cells (MSCs) have the ability to suppress unwanted immune responses. If MSCs are pre-treated with cytokines, they can do this even better. Typically, MSCs are pre-treated with a molecule called interferon-γ. This molecule stimulates MSCs and causes then to suppress the immune response, but it also causes MSCs to express proteins that cause them to be rejected by the immune system. Thus interferon-γ seems to cause problems that prevent the MSCs from working properly.

In a really beautiful paper by Kisha Sivanathan in the Coates lab at the School of Medical Sciences, Adelaide, Australia and her colleagues, showed that pre-treating human MSCs with interleukin-17A did a better job at stimulating MSCs without sensitizing the cells to the immune system.

When Sivanathan and her co-workers treated human bone marrow-derived MSC with interleukin-17A, this molecule enhanced the ability of MSCs to suppress the immune response without making the MSCs subjects for rejection by the immune system.  These interleukin-17A-treate MSCs (MSC-17s) showed no induction or upregulation of molecules that the immune system reacts against (MHC class I, MHC class II, and T cell costimulatory molecule CD40), and the the interleukin-17A-treated MSCs maintained normal MSC morphology and made all the common MSC markers.

When MSC-17s were placed in culture with activated human T cells, the MSCs-17s potently suppressed T cell proliferation.  Additionally, MSC-17s prevented activated T-cells from making the whole cocktail of molecules they normally make once they are activated.

Not all T-cells are created equal. There is a group of T-cells called “regulator T-cells” or T-regs for short. T-regs tend to down regulate the immune response. It turns out that MSCs-17s turn on T-regs and stimulate them to potently suppress T-cell activation. They do this without inducing immunogenicity in the MSCs.

Thus, pre-treating MSCs with interleukin-17A represents a superior way for stimulate MSCs to suppress T cell activity in clinical situations.  Dr. Coates and his colleagues are hopeful that this protocol can be the subject of clinical trials in the near future.

Human Umbilical Cord Mesenchymal Stem Cells and Rheumatoid Arthritis

A collaborative study between physicians at the Hospital of Chinese People’s Liberation Army and the University of Oklahoma Health Sciences Center has examined the efficacy of umbilical cord mesenchymal stem cell treatments in combination with drugs in patients with active rheumatoid arthritis (RA).

RA may exist in 0.5-1.0% of the general population. In 2005, an estimated 1.5 million US adults aged ≥ 18 (0.6%) had RA. RA is characterized by chronic inflammation of the joints that causes cartilage and bone damage and deformity. It occurs in women two to three times more often than men.

Treatment of RA requires the administration of disease-modifying antirheumatic drugs (DMARDs), Unfortunately, these drugs have sizable side effects, and less debilitating treatments would be a welcome addition to the treatment options for RA patients.

A paper by Liming Wang and colleagues that was published in Stem Cells and Development examines the efficacy of combining DMARDs with infusions of umbilical cord mesenchymal stem cells (MSCs). Since MSCs have the ability to suppress an overactive immune response, such treatments might provide relief from the symptoms of RA and decrease the dependence on DMARDs.

In this study, Wang and others enrolled 172 RA patients and divided them into two groups: 36 of them were treated with DMARDs alone and 136 were treated with DMARDs plus umbilical cord MSCs (UC-MSCs). Of these 136 patients, 76 were treated for 3 months, 45 for 6 months, and 15 for 8 months. Each of these groups consisted of patients who could and who could not tolerate DMARDs. All patients in the second group received 4 x 10[7] UC-MSCs in 40 milliliters of liquid, but the first group received stem cell “solvent” (whatever that is) without UC-MSCs.

The results clearly showed that UC-MSCs treatments are safe. Patients blood work-ups before and after treatment show no significant differences. Secondly, the DMARD-only group did not show any improvements, but they did not get worse either. The DMARD + UC-MSC group showed quantifiable improvements. These patients reported feeling better in health assessment questionnaires, their serum levels of C-reactive protein and rheumatoid factor went down and their numbers of regulatory T-cells went up. The joint evaluations of these patients also improved (the so-called DAS28 score). All of these are measures of the severity of RA, and in the DMARD + UC-MSC groups, all the these markers improved.

Other markers of RA severity such as IL-6 and TNF-alpha also decreased in the DMARD + UC-MSC patients.

From these data, Wang and others conclude that “UC-MSCs are suitable pllications in the clinic and provide an additional choice to many RA patients.”

The data in this paper are rather clear. The benefits of a single UC-MSC treatment are significant. For this reason, umbilical cord MSCs should be regarded as a potential adjuvant treatment for RA patients.