Синдром "трансплантат против хозяина": причины, проявления и лечение.

Graft versus host disease (GvHD) is a syndrome, characterized by inflammation in different organs. GvHD is commonly associated with bone marrow transplants and stem cell transplants. White blood cells of the donor's immune system which remain within the donated tissue (the graft) recognize the recipient (the host) as foreign (non self). The white blood cells present within the transplanted tissue then attack the recipient's body's cells, which leads to GvHD. This should not be confused with a transplant rejection, which occurs when the immune system of the transplant recipient rejects the transplanted tissue; GvHD occurs when the donor's immune system's white blood cells reject the recipient. The underlying principle (alloimmunity) is the same, but the details and course may differ. GvHD can also occur after a blood transfusion, known as Transfusion associated graft versus host disease or TA GvHD if the blood products used have not been gamma irradiated or treated with an approved leukocyte reduction system. In contrast to organ/tissue transplant associated GvHD, the incidence of TA GvHD is increased with HLA matching (first degree or close relatives).

In the clinical setting, graft versus host disease is divided into acute and chronic forms, and scored or graded on the basis of the tissue affected and the severity of the reaction. In the classical sense, acute graft versus host disease is characterized by selective damage to the liver, skin (rash), mucosa, and the gastrointestinal tract. Newer research indicates that other graft versus host disease target organs include the immune system (the hematopoietic system, e. g., the bone marrow and the thymus) itself, and the lungs in the form of immune mediated pneumonitis. Biomarkers can be used to identify specific causes of GvHD, such as elafin in the skin. Chronic graft versus host disease also attacks the above organs, but over its long term course can also cause damage to the connective tissue and exocrine glands. Mucosal damage to the vagina can result in severe pain and scarring, and appears in both acute and chronic GvHD. This can result in an inability to have sexual intercourse.

The acute or fulminant form of the disease (aGvHD) is normally observed within the first 10 to 100 days post transplant, and is a major challenge to transplants owing to associated morbidity and mortality. This is typically diagnosed via intestinal biopsy. Liver GvHD is measured by the bilirubin level in acute patients. Skin GvHD results in a diffuse red maculopapular rash, sometimes in a lacy pattern. Acute GvHD is staged as follows: overall grade (skin liver gut) with each organ staged individually from a low of 1 to a high of 4. Patients with grade IV GvHD usually have a poor prognosis. If the GvHD is severe and requires intense immunosuppression involving steroids and additional agents to get under control, the patient may develop severe infections

The chronic form of graft versus host disease (cGvHD) normally begins 90 to 600 days post transplant. The first symptom of cGvHD is commonly a rash on the palms of the hands or the soles of the feet, and the rash can spread and is usually itchy and dry. In severe cases, the skin may blister and peel, like a bad sunburn. A fever may also develop. Other symptoms of chronic GVHD can include: in comparison to the classical oral lichen planus. Oral cancer associated with graft versus host disease may have more aggressive behavior with poorer prognosis, when compared to oral cancer in non hematopoietic stem cell transplantation patients. An immuno competent graft is administered, with viable and functional immune cells. The recipient is immunologically different from the donor – histo incompatible. The recipient is immunocompromised and therefore cannot destroy or inactivate the transplanted cells. In particular, it involves an inability of the recipient's cell mediated immunity to destroy or inactivate viable lymphocytes from the donor. After bone marrow transplantation, T cells present in the graft, either as contaminants or intentionally introduced into the host, attack the tissues of the transplant recipient after perceiving host tissues as antigenically foreign. The T cells produce an excess of cytokines, including TNF α and interferon gamma (IFNγ). A wide range of host antigens can initiate graft versus host disease, among them the human leukocyte antigens (HLA). However, graft versus host disease can occur even when HLA identical siblings are the donors. HLA identical siblings or HLA identical unrelated donors often have genetically different proteins (called minor histocompatibility antigens) that can be presented by major histocompatibility complex (MHC) molecules to the donor's T cells, which see these antigens as foreign and so mount an immune response. Antigens most responsible for graft loss are HLA DR (first six months), HLA B (first two years), and HLA A (long term survival). While donor T cells are undesirable as effector cells of graft versus host disease, they are valuable for engraftment by preventing the recipient's residual immune system from rejecting the bone marrow graft (host versus graft). In addition, as bone marrow transplantation is frequently used to treat cancer, mainly leukemias, donor T cells have proven to have a valuable graft versus tumor effect. A great deal of current research on allogeneic bone marrow transplantation involves attempts to separate the undesirable graft vs host disease aspects of T cell physiology from the desirable graft versus tumor effect.

This type of GvHD is associated with transfusion of un irradiated blood to immunocompromised recipients. It can also occur in situations in which the blood donor is homozygous and the recipient is heterozygous for an HLA haplotype. It is associated with higher mortality (80–90%) due to involvement of bone marrow lymphoid tissue, however the clinical manifestations are similar to GVHD resulting from bone marrow transplantation. Transfusion associated GvHD is rare in modern medicine. It is almost entirely preventable by controlled irradiation of blood products to inactivate the white blood cells (including lymphocytes) within.

Thymus transplantation may be said to be able to cause a special type of GvHD because the recipient's thymocytes would use the donor thymus cells as models when going through the negative selection to recognize self antigens, and could therefore still mistake own structures in the rest of the body for being non self. This is a rather indirect GvHD because it is not directly cells in the graft itself that causes it but cells in the graft that make the recipient's T cells act like donor T cells. It can be seen as a multiple organ autoimmunity in xenotransplantation experiments of the thymus between different species. Autoimmune disease is a frequent complication after human allogeneic thymus transplantation, found in 42% of subjects over one year post transplantation. However, this is partially explained by the fact that the indication itself, that is, complete DiGeorge syndrome, increases the risk of autoimmune disease.

A GvHD like disease called thymoma associated multiorgan autoimmunity (TAMA) can occur in patients with thymoma. In these patients rather than a donor being a source of pathogenic T cells, the patient's own malignant thymus produces self directed T cells. This is because the malignant thymus is incapable of appropriately educating developing thymocytes to eliminate self reactive T cells. The result is a disease virtually indistinguishable from GvHD.

DNA based tissue typing allows for more precise HLA matching between donors and transplant patients, which has been proven to reduce the incidence and severity of GvHD and to increase long term survival. The T cells of umbilical cord blood (UCB) have an inherent immunological immaturity, and the use of UCB stem cells in unrelated donor transplants has a reduced incidence and severity of GvHD. Methotrexate, cyclosporin and tacrolimus are common drugs used for GvHD prophylaxis. Further research is necessary to evaluate whether mesenchymal stromal cells can also be used for the prophylaxis. Graft versus host disease can largely be avoided by performing a T cell depleted bone marrow transplant. However, these types of transplants come at a cost of diminished graft versus tumor effect, greater risk of engraftment failure, or cancer relapse, and general immunodeficiency, resulting in a patient more susceptible to viral, bacterial, and fungal infection. In a multi center study, disease free survival at 3 years was not different between T cell depleted and T cell replete transplants.

Intravenously administered glucocorticoids, such as prednisone, are the standard of care in acute GvHD and chronic GVHD. The use of these glucocorticoids is designed to suppress the T cell mediated immune onslaught on the host tissues; however, in high doses, this immune suppression raises the risk of infections and cancer relapse. Therefore, it is desirable to taper off the post transplant high level steroid doses to lower levels, at which point the appearance of mild GVHD may be welcome, especially in HLA mis matched patients, as it is typically associated with a graft versus tumor effect While glucocorticoids remain the first line of treatment for acute GVHD, only about 50% of patients respond to treatment, otherwise having steroid refractory GVHD (SR GVHD). An increasing number of recent treatment options for SR GVHD have been investigated, such as extracorporeal photopheresis (ECP), mesenchymal stem cell (MSCs), fecal microbial transplantation (FMT), and the medication Ruxolitinib. Standard prophylaxis involves the use of cyclosporine for six months with methotrexate. Cyclosporin levels should be maintained above 200 ng/ml. Other substances that have been studied for GvHD treatment include, for example: sirolimus, pentostatin, etanercept, and alemtuzumab.

There are a large number of clinical trials either ongoing or recently completed in the investigation of graft versus host disease treatment and prevention. On May 17, 2012, Osiris Therapeutics announced that Canadian health regulators approved Prochymal, its drug for acute graft versus host disease in children who have failed to respond to steroid treatment. Prochymal is the first stem cell drug to be approved for a systemic disease. In January 2016, Mesoblast released results of a phase 2 clinical trial on 241 children with acute Graft versus host disease, that was not responsive to steroids. The trial was of a mesenchymal stem cell therapy known as remestemcel L or MSC 100 IV. Survival rate was 82% (vs 39% of controls) for those who showed some improvement after one month, and in the long term 72% (vs 18% of controls) for those that showed little effect after one month.