Graft-versus-Host Response

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Classification according to ICD-10
T86.01 Acute graft-versus-host disease, grades I and II
T86.02 Acute graft-versus-host disease, grades III and IV
T86.03 Chronic graft-versus-host disease, limited form
T86.04 Chronic graft-versus-host disease, pronounced form
T86.09 Graft-versus-host disease, unspecified
ICD-10 online (WHO version 2019)

Under the Graft-versus-Host Reaction (GvHR; German: graft -gegen- host reaction ; English: graft-versus-host disease (GVHD)) refers to an immunological response that subsequently an allogeneic bone marrow or stem cell transplantation can occur. In GvHR, it is primarily the donor's T lymphocytes contained in the transplant that react against the recipient organism. Symptoms of GvHR most commonly manifest themselves on the skin , liver , intestines and eyes . The GvHR is divided into four degrees of severity according to the severity and number of organs involved.

Pathogenesis

Many mechanisms and explanations for the development of GvHR have been obtained from pre-clinical animal models. In order to perform a stem cell transplant , hematopoietic stem cells from the bone marrow and T cells must be conditioned . Conditioning with chemotherapy or whole-body irradiation damages the epithelial barriers of the recipient's organs, especially those of the gastrointestinal tract . Microorganisms and associated PAMPs can penetrate deeper tissue layers. There are discovering pattern recognition receptors ( Pattern Recognition Receptors ) of various immune cells to and activate the immune system via cytokines .

Interferon-γ is an important mediator in the development of the immune reaction that triggers GVHD . The signal transmission takes place primarily via the JAK-STAT signal path , especially when the dendritic cells and neutrophils are activated . Associated with the acute GVHD tissue damage also be further pro-inflammatory cytokines controlled, the effects also on Janus kinase -associated (JAK) cytokine receptors are transmitted.

Graft-versus-malignancy effect

While GvHR is an undesirable reaction of the donor lymphocytes to the host organism, the reaction directed against malignant cells is also called "Graft-versus-Leukemia" (GvL) or more generally "Graft-versus-Malignancy" (GvM), quite desirable. The donor's CD 56 + / CD3- NK cells are primarily responsible for this reaction - they are able to lyse cancer cells even without specific antigen recognition. The function of the NK cells is regulated by the interplay of various stimulating and inhibiting cell-cell interactions. Recently, the group of immunoglobulin-like receptors (KIRs) in particular has attracted scientific interest. These surface receptors are expressed by NK cells and recognize epitopes typical of the MHC -I complex.

The main ligands for inhibitory KIR receptors are the HLA-C molecules, which are found on many cells in the body. The KIR-HLA interaction is subject to a high genetic polymorphism. From this point of view, HLA-C compatibility is important for hematopoietic stem cell transplants - if the recipient's cells are not able to express the appropriate KIR ligands, these cells become the target of the NK cell action that inevitably leads to cell death.

In theory, this incompatibility should therefore, in addition to the desired effects of the GvL reaction, also contribute to a generalized occurrence of GvHR; paradoxically this is not the case. As Italian doctors were able to show, the incompatibility of the KIR ligands in a familial-allogeneic stem cell transplant was actually related to the occurrence of alloreactive NK cells that could not be blocked by the MHC-I complex of the recipient cells - such a constellation However, it led to a reduced recurrence rate in high-risk AML patients without significantly increasing the risk of GvHD or a graft defect.

Polish researchers came to similar results when they examined 130 patients who had received allogeneic stem cell transplants from unrelated donors. In this context, English researchers were able to identify the recipient's HLA-C characteristics as an important prognostic factor in a retrospective examination of 220 stem cell transplants between HLA-compatible twins in myeloid and lymphatic diseases.

Difference Between Acute and Chronic GVHD

Risk factors for developing GVHD
Acute GVHD Chronic GVHD
  • HLA mismatch transplantation
  • peripheral blood stem cell transplant (versus bone marrow transplant)
  • higher age of donor and recipient
  • Foreign donor transplant
  • female donor, male recipient
  • certain conditioning regimes
  • HLA mismatch transplantation
  • peripheral blood stem cell transplant (versus bone marrow transplant)
  • higher age of donor and recipient
  • previous acute GVHD
  • previous infections

A distinction must be made between acute and chronic GVHD. Chronic GVHD (cGVHD) is a protracted reaction of the donor immune system against tissue of the recipient that usually begins 2 to 18 months after an allogeneic stem cell transplant (hereinafter: allo-Tx). About 50% of allogeneic stem cell transplant patients suffer from chronic GVHD. Acute GVHD (aGVHD) usually occurs within the first 100 days after allo-Tx. However, there is also the so-called late onset aGVHD that occurs after day 100 and the recurrent or persistent aGVHD.

Epidemiology

The risk of developing GvHR is closely related to compatibility, which is determined by the human leukocyte antigen ( HLA ). In the case of allogeneic transplantation from HLA-identical sibling donors, however, approx. 30 to 40% of the patients develop a mild to moderate acute GvHR despite optimal preventive measures; approx. 10% suffer from GvHR that is difficult to control. Various transplant preparation techniques have reduced the risk of GvHR and early treatment-related mortality (TRM), but they did not lead to a measurable increase in survival.

Chronic GVHD occurs in about half of patients. Graft-versus-host disease - especially the chronic form - is (partly) responsible for around 25% of deaths after transplantation.

The known risk factors for the occurrence of chronic or acute GVHD are listed in the adjacent table. Some risk factors are the same for both forms of GVHD, while others are different.

Symptoms

The symptoms consist of inflammatory reactions in all organs, often accompanied by a high fever. The skin in particular reacts with rashes, peeling and flaking of the upper layers of the skin up to deep lesions. The mucous membranes of the digestive tract become inflamed, which leads to mucositis in the mouth and gastritis in the stomach with a tendency to nausea and vomiting; the inflamed intestinal lining causes diarrhea. The dysfunction of the liver causes jaundice . Chemosis , hemorrhagic or pseudomembranous conjunctivitis can occur in the eye . The latter are signs of a generalized spread of the immune reaction and thus an indication of a rather poor prognosis .

treatment

The standard therapy of treatment is systemic high-dose cortisone therapy with a response of 60% in the second-degree GVHD and 30–40% in the fourth-degree severity. In addition, other immunosuppressants such as ciclosporin , antimetabolites and monoclonal antilymphocyte antibodies are used. Photopheresis is used as a second line therapy . Although GvHR poses a considerable health risk in allogeneic stem cell or bone marrow transplants, a moderate form of GvHR can also benefit the recipient, as T cells in the transplant also destroy any remaining tumor cells in the host ( graft-versus-malignancy effect ).

Also ruxolitinib , an oral selective inhibitor of Janus kinases JAK-1 and JAK-2, via the JAK-STAT signaling pathway is involved in the development of acute GVHD, is in clinical trials have a good effect, but is not yet approved for this indication . After thirty years and numerous negative study results, it is the first drug to show a clear positive effect in the treatment of GVHD. In a multicentre, open, randomized controlled study (phase III study) led by the Freiburg University Hospital , a positive effect of ruxolitinib was achieved after 28 days in 62% (versus 39% in the control group) ( odds ratio 2.64, confidence interval 1 , 65 - 4.22) with a median survival time of 11.1 months (versus 6.5 months). A cytomegalovirus reactivation was observed in 26% (from 21%), moreover, showed a thrombocytopenia in 33% to 18%, and anemia in 30% and 28%.

Guidelines

The current status of the diagnosis and treatment of acute and chronic GVHD is summarized in two Onkopedia guidelines.

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  20. ↑ [1] Onkopedia guidelines for acute and chronic GvHD (accessed on December 16, 2015)