Stem Cells Get Rid of Graft vs Host Disease

A New story has just broke in new scientist (yes, that is where i get all my science news... but for f*#ks sake it's the only news outlet that makes the effort to cite their original article sources.)

A clinical trial has just been done in which stem cells have been used to combat graft vs host disease.




What is Graft vs Host Disease

There are some diseases which affect white blood cells, and red blood cells. These include Sickle Cell anaemia, Leukaemia and countless other diseases. In some cases, the only way to cure these diseases is to have a bone marrow transplant operation.
Bone marrow is where all the blood cells originate, and contains hemapoietic stem cells (blood-making stem cells) If this is not producing functional white blood cells (e.g. in Severe Combined Immunodeficiency) or producing malfunctioning or dangerous white blood cells (leukaemia, and sickle cell anaemia), it can be replaced in a bone marrow transplant operation.
So a person (usually within the same family as the sufferer) will donate some bone marrow to the sick individual. if all goes well, this new bone marrow will grow and will cure the patients disease.
However, sometimes there are some of the donor's immune cells left over in the bone marrow graft. These cells are designed to recognise any antigen that does not belong to their host. So when they are placed in a new host, it is likely that they will see some antigens that they have never seen before, and they will start to attack the new host. This is Graft vs Host Disease.
The general way to tackle this disease is by depleting the levels of T-cells from the bone marrow transplants, and depressing the patient's immune system with drugs such as cyclosporin A.
However this is not a watertight treatment, and it is still possible to get Graft vs Host Disease after this

So How Can Stem Cells Help With This Disease ?


The popular definition of a stem cell is a cell which can "divide and differentiate into another type of cell". But this function is not very useful in Graft vs Host Disease, as the problem is with the immune system, and not with any particular cell deficiency.

However, some types of stem cells have different functions within the body, and don't just "replenish and grow". If that function could serve a purpose, it would surely be solved via an infusion of haemopoietic stem cells, which are found in the bone marr... oh wait.

However, a different type of stem cell exists, known as the Mesenchymal Stem Cell.

What are Mesenchymal Stem Cells ?

Mesenchymal stem cells are found in the bone marrow, although at a relatively low concentration (0.01-0.001% of the stem cell population) [1]. They differentiate into bone cells, cartilage cells, and bone marrow stromal cells.
However, they are more commonly found in the umbilical cord blood [3], and it is believed that they circulate through the babay and the mother during pregnancy [2], and these cells engraft in the mothers bone marrow. The extraordinary thing about this is that they do this without eliciting a host vs graft or graft vs host reaction. In fact, these cells can live in the mother up to ten years after pregnancy.

How do they do this?

It is thought that mesenchymal stem cells can act to modulate the immune system. it has been that they are able to block T-cell reactions, and prevent the rejection of a skin graft in baboons.[4]
In fact the degree of tolerance that these stem cells are capable of achieving is good enough to support a xenogeneic transplant, i.e. a transplantation between two species (rat and mouse) [6]
These cells have also been used to treat a patient for osteogenesis imperfecta [5], even though the tissue types of the donor and the host were vastly different.
it is thought that they cause tolerance through emitting special cytokines, like TGF-β and other products. the actual mechanism throuh which they induce this tolerance is still under investigation.

What's on the Market?

A mesenchymal stem cell therapy marketed by Osiris therapeutics, known as Prochymal is currently in development.
Prochymal consists of mesenchymal stem cells prepared from the bone marrow of healthy donors.
In the phase 2 trial, 32 patients with graft vs host disease were treated with experimental infusions of this product in conjunction with steroid therapy, alongside a control group which recieved only steroid therapy.
of the treated patients, 72% showed a complete resolution of clinical symptoms, with 19% showing a partial effect and the remaining percentage with no effect.
These are incredibly encouraging results, and now a Phase 3 clinical trial has started. This Double Blind Randomised control trial may make or break this product.

If this trial does go really well, it will open up a whole can of worms in medicine.
For a start, mesenchymal stem cells can be used to help in a whole variety of tissue transplant situations. they can be used to help healing wounds, repairing bone. These cells have been used in the lab as a gene therapy delivery system. The whole face of medicine could be changed

However, let's not get too excited about this. One problem with basing therapies off any form of stem cells is that you need a reliable source for them. You can't simply extract the stem cells from one person, grow them up in culture and solve the problems of the world. For a start, cells dividing in culture acquire mutations. So you may end up accidentally giving a patient dangerously mutated stem cells.

The only way to prevent this is to make sure that lots of people give bone marrow. A bone marrow extraction operation is incredibly painful. Considering how many people turn up for blood donation, you can't really expect a great outpouring of people to give their bone marrow.
On the other hand, many people are happy to donate the umbilical cords of their babies, and these have been found to be quite rich in mesenchymal stem cells. the only problem is that these cells are a quite temperamental, and harder (and therefore more expensive) to work with. Nevertheless, there are umbilical cord blood banks in operation at the moment, whoch freeze the blood sample from the cord, and preserve them, until such time that cord blood based stem cell therapy becomes sufficiently advanced.
I have high hopes, but time will tell whether they are validated or not.

1. Campagnoli C, Roberts IAG, Kumar S, Bennett PR, Bellantuono I, Fisk NM: Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone Marrow. Blood 2001, 98(8):2396-2402.
2. O'Donoghue K, Chan J, de la Fuente J, Kennea N, Sandison A, Anderson JR, Roberts IAG, Fisk NM: Microchimerism in female bone marrow and bone decades after fetal mesenchymal stem-cell trafficking in pregnancy. Lancet 2004, 364(9429):179-182.
3.Erices A, Conget P, Minguell JJ: Mesenchymal progenitor cells in human umbilical cord blood. British Journal of Haematology 2000, 109(1):235-242.
4. Bartholomew A, Sturgeon C, Siatskas M, Ferrer K, McIntosh K, Patil S, Hardy W, Devine S, Ucker D, Deans R et al: Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Experimental Hematology 2002, 30(1):42-48.
5.Le Blanc K, Gotherstrom C, Ringden O, Hassan M, McMahon R, Horwitz E, Anneren G, Axelsson O, Nunn J, Ewald U et al: Fetal mesenchymal stem-cell engraftment in bone after in utero transplantation in a patient with severe osteogenesis imperfecta. Transplantation 2005, 79(11):1607-1614.
6.Saito T, Kuang JQ, Bittira B, Al-Khaldi A, Chiu RCJ: Xenotransplant cardiac chimera: Immune tolerance of adult stem cells. Annals of Thoracic Surgery 2002, 74(1):19-24.