Graft vs Host Disease
Graft-versus-host disease (GVHD) is defined as a syndrome in which cells originating from a donor recognize and mount a deleterious immune response against antigens found in the immunocompromised recipient. The disease presents as a heterogeneous condition involving multiple organs, most commonly the skin, mucosa, gastrointestinal tract, liver and lungs. For patients undergoing allogeneic hematopoietic stem cell transplant (HSCT), GVHD is a significant cause of morbidity and mortality; up to 80% of patients will develop GVHD at approximately 14 -21 days following HSCT (acute), and of those surviving beyond 100 days, between 30 and 70% will develop chronic GVHD. Unsurprisingly, chronic GVHD represents the single leading cause of death in HSCT survivors.
Development of GVHD is dependent on the activation of antigen-specific donor T cells that are able to mount a specific immune response targeting host tissues. This event is potentiated by conditioning of the host prior to HSCT in order to suppress the immune system and ensure effective engraftment.
The focus of current therapy is general immune suppression using corticosteroids, which has dubious efficacy; sustained amelioration of disease symptoms are only seen in around 50% of patients. More promising therapies are based on the prophylactic prevention of GVHD, and use T cell targeting agents such as methotrexate, tacrolimus, and JAK/STAT inhibitors.
Recipient mice are pre-conditioned with a lethal dose of total body irradiation prior to the adoptive transfer of T-cell depleted bone marrow supplemented with splenocytes harvested from an MHC-mismatched donor mouse. Following transplant, the mice rapidly lose weight due to the conditioning regimen and then partially recover by day 14, after which they develop a progressively worsening disease characterized by weight loss and increasing GVHD score. Endpoint survival in untreated mice is approximately 50%.
Study Design Table
Model | Description | Duration | Endpoints |
---|---|---|---|
Allogeneic Bone Marrow Transplant | GVHD reaction is assessed using a 5-criteria score. Initial recovery from conditioning regimen is followed by progressive exacerbation of disease from day 14 onwards | 5-8 Weeks | GVHD score, Weight, Survival, Histology |
Representative data below, click images to enlarge.
Recipient severely immunocompromised (NSG) mice are injected with a pre-determined number of purified single-donor human PBMCs. Following transplant, the mice develop a progressively worsening disease characterized by weight loss and increasing GVHD score. Endpoint survival in untreated mice is determined by the number of cells injected. Cryopreserved PBMCs from identified donors are available for maximizing continuity across multiple studies.
Study Design Table
Model | Description | Duration | Endpoints |
---|---|---|---|
Human PBMC Xenograft | GVHD reaction is assessed using a 5-criteria score. Progressive exacerbation of disease is seen from day 14 onwards | 5-8 Weeks | GVHD score, Weight, Survival, Histology |
Representative data below, click images to enlarge.
Recipient C57Bl/6 mice are pre-conditioned with high dose of total body irradiation prior to the adoptive transfer of bone marrow supplemented with splenocytes harvested from an MHC-mismatched donor mouse (LP/J). Following irradiation and transplant, the recipient mice show transient mild weight loss followed by recovery up to approximately day 21 to 28, after which they develop a progressively worsening disease characterized by weight loss, increasing GVHD score, and development of sclerodermatous skin lesions. Animals are monitored up to day 60; endpoint survival in untreated mice is approximately 50%.
Study Design Table
Model | Description | Duration | Endpoints |
---|---|---|---|
Allogeneic Bone Marrow Transplant | GVHD reaction is assessed using a modified 5-criteria score. Initial recovery from conditioning regimen is followed by progressive exacerbation of disease from day 21-28 onwards | 9-10 Weeks | GVHD score, Weight, Survival, Histology |
Representative data below, click images to enlarge.
While a HSCT can result in the life-threatening complication of GVHD, it can also provide a beneficial effect to the host known as the Graft versus Leukemia (GVL) effect in which the T-cells in the donor cell population target and kill malignant cells in the host. This phenomenon can be demonstrated in the allogeneic bone marrow transplant model of GVHD when tumor cells are injected shortly after cell transplant. When T cells are present in the cell transplant, tumors fail to grow. Tumor cells will only grow in this model when T-cells are depleted from the cell transplant. This allows clients to assess whether treatments in this GVHD model have any effect on the GVL phenomenon.
Study Design Table
Model | Description | Duration | Endpoints |
---|---|---|---|
Graft versus Leukemia | Following induction of GVHD by allogeneic cell transplant, tumor cells are implanted, and their growth is observed. | 4-8 Weeks | Tumor size, tumor bioluminescence, GVHD score, weight, survival, histology |
Representative data below, click images to enlarge.