Graft vs. Host Disease (GVHD)

Clinical Background

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 and tacrolimus.
 
 

Preclinical Models

Model Description Length 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 8 weeks GVHD score, weight, survival, histology

 
 

Allogeneic Bone Marrow Transplant -Induced GVHD

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 lymphocytes harvested from an MHC-mismatched donor mouse. Following transplant, the mice rapidly lose weight due to the conditioning regimen and then 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%.
 
 

Percentage Weight Change

Recipient mice were pre-conditioned and transplanted with 1x107 donor-derived CD3-depleted bone marrow cells supplemented with different numbers of splenocytes (see legend) on day 0. Weights were recorded daily and the percent weight change relative to day 0 was calculated. AUC: area under the curve; n=15 per group; data is presented as mean ±SEM.

 

GVHD Scoring Scale for Disease Evaluation

 

GVHD Score

Recipient mice were pre-conditioned and transplanted with 1x107 donor-derived CD3-depleted bone marrow cells supplemented with different numbers of splenocytes (see legend) on day 0. GVHD score was recorded daily. AUC: area under the curve; n=15 per group; data is presented as mean ±SEM.

 

Percent Survival

Recipient mice were pre-conditioned and transplanted with 1x107 donor-derived CD3-depleted bone marrow cells supplemented with different numbers of splenocytes (see legend) on day 0. Treated mice (α-p40 mAb and Tacrolimus) received bone marrow plus 2x106 splenocytes. Survival was recorded daily. n=15 per group.