Aplicaciones: 80

Stem cells are precursor cells that can divide and differentiate into specialized cells types in the body such as a muscle cell, a red blood cell, or a brain cell. They can self-renew to produce more stem cells and to replenish others (Marieb 2004, Stem Cell Basics: Introduction 2009). There are three types of human stem cells: embryonic, embryonic germ, and adult. The embryonic and embryonic germ stem cells develop at early stage of development, approximately five days and five to nine weeks, respectively. Adult stem cells are found in developed tissue, for example the haematopoietic stem cells (Marieb 2004).

Haematopoietic stem cells (HSCs) are a type of stem cells that form blood and immune cells. They have the properties to replenish all blood cell types and to self- renew (M¨uller-Sieburg et al. 2002, Hematopoietic Stem Cells 2001). HSCs are found mainly in the bone marrow of adults, that is the spongy tissue in the interior of bones, and also in peripheral, circulating blood. HSCs are nowadays used as a therapy. HSC transplants are used as a therapy mainly in patients with haematological malignant diseases, i.e. cancer of the blood and immune systems, such as leukaemia and lymphoma, which result from the uncontrolled proliferation of white blood cells (Hematopoietic Stem Cells 2001).

Haematopoietic stem cell transplantation (HSCT) is a medical procedure to replace the cells destroyed by radiotherapy or chemotherapy in patients with haematological malignant diseases. Sources to collect HSCs are the bone marrow or peripheral blood. The HSCs are collected from the same patient (autologous transplant) or from a donor (allogeneic transplant). In the case of allogeneic transplant, a donor can be related (usually a sibling) or unrelated to the patient (Hematopoietic Stem Cells 2001, Copelan 2006). In this context, the transplanted HSCs are also called allogeneic graft, and the patient undergoing the HSCs transplant is called host. The donor tissue type has to be compatible with that of the patient, since severe immune reactions may occur, the severity of which is dependent on the extent of incompatibility. On this matter, matching of the human leukocyte antigen (HLA) between patients and donors is crucial.

Antigen is a substance that is recognized as foreign and activates the immune sys- tem (Marieb 2004). The HLA is the major histocompatibility complex (MHC) in humans. The MHC helps the immune system protecting the body by recognizing proteins from the own individual, and proteins from foreigners such as viruses and bacteria. MHC consists of three classes genes located on chromosome 6, Class I (the main genes are HLA-A, -B, and -C), Class II (the main genes are of the types HLA-DP, -DQ, and -DR), and Class III (these genes encode components of the so called complement system) (HLA gene family 2009).

Class I genes produce proteins that are found on almost all cell’s surface, these proteins bind to peptides (fragments of proteins) from inside the cells and display them to T cells. T cells are white blood cells known as lymphocytes. Cytotoxic T cells (TC cells, a type of T cells) destroy cells whose peptides are recognized

as foreigners. Hence, under HLA mismatch between donor and patient, TC cells

from the patient recognize peptides of the donor cells as foreigners and cause graft rejection. Likewise, TC cells from the donor recognize peptides of the patient cells as

foreigners and cause Graft-versus-Host Disease (GvHD) (Graft-versus-host disease 2011, HLA gene family 2009).

Class II genes produce proteins that are found on the cell’s surface of certain cells of the immune system. These proteins bind to peptides from outside the cells and display them to the T cells. Recognition of foreigner peptides stimulate production of helper T cells (THcells, a type of T cells), which in turn stimulate proliferation of

B cells. B cells produce antibodies to the foreigner peptides, the antigens. Antibod- ies cannot destroy antigens, but they can inactivate and tag them for destruction (Marieb 2004, HLA gene family 2009).

Two types of GvHD can appear: acute and chronic GvHD (aGvHD and cGvHD). aGvHD is normally observed within few weeks (the first 100 days) after transplant. It affects the liver, skin, and gastrointestinal tract (Graft-versus-host disease 2011). cGvHD is normally observed after 100 days. Organs commonly affected include the skin, mouth, liver, eyes, gastrointestinal tract, lung, and oesophagus (Lee and Flowers 2008).

of care. However, it is usually difficult to find full HLA-matched unrelated donors. HSC transplants are still a problem for the association with GvHD on that group of patients, more than with sibling donors (Riddell and Appelbaum 2007).

Types of treatments are used to prepare a patient for stem cell transplantation, these treatments are called conditioning regimens (conditioning regimen 2011), which in- fluence the prevention of GvHD. Myeloablative regimens such as total-body irradi- ation are designed to kill all residual cancer cells in the body of the patient. This causes immunosuppression (reduction of the activity of the immune system), that reduces chances of graft rejection, and favours engraftment in allogeneic transplan- tation. The drawback of myeloablative regimens is that since it lowers activity of the immune system, there is lower reaction against foreigners, such as viruses, which increases the chance of fatal post-transplant infections, i.e. it increases transplant related mortality (TRM).

Non-myeloablative regimens use doses of chemotherapy and radiation much lower than those of myeloablative regimens. These regimens rely on a graft-versus-tumour (GvT) effect to kill tumour cells with donor T cells. Reduced-intensity regimens vary between myeloablative to non-myeloablative. The advantage of both reduced- intensity and non-myeloablative regimens is the decreased toxicity as well as a lower chance of infections and TRM. However, relapse (returning of the disease) increases since remaining tumoural cells proliferate again, unless tumoural cells were elimi- nated by the GvT effect (Conditioning Regimens 2011).

Another way of preventing GvHD has been focused on T cell removal from donor stem cells. This is called T cell depletion. On one side, it helps reducing the occurrence of GvHD, since there is no reaction of the graft to the host cells, but it increases the possibility of graft rejection. On the other side, since there is no activity of the immune system from donor stem cells, no GvT effect takes place, which increases the chances of relapse (Riddell and Appelbaum 2007).

Even if conditioning regimens and T cell depletion can improve post-transplant problems with GvHD, it has not been demonstrated that these ways of preventions improve survival (Riddell and Appelbaum 2007). The overall survival of patients after HSCT is not yet encouraging. The survival rate is about 40-60%at 5 years after transplant. As described above, adverse clinical outcomes such as GvHD, infections are further TRM are problems that diminish the success of the transplants.