Sclerodermatous Chronic GVHD (Minor MHC Mismatch Sclerodermatous Chronic GVHD)

Description

The sclerodermatous chronic GVHD model is a minor MHC mismatched model commonly used to study pathogenesis of fibrosis in cGVHD, and frequently used in drug discovery and development. Sclerodermatous Chronic GVHD model pathology involves immune cell mediated release of Th2 cytokines and fibrosis pathways. Recipient C57Bl/6 mice are pre-conditioned with a lethal dose of total body irradiation (TBI) prior to the adoptive transfer of bone marrow that is supplemented with splenocytes harvested from a minor MHC-mismatched donor mouse (LP/J). Following irradiation and transplant, the recipient mice show transient weight loss that typically recovers by Day 21 to 28. After this 3-4 week period, animals develop a progressively worsening GVHD that is characterized by weight loss, increasing GVHD score, and development of sclerodermatous skin lesions. Test article responses can be compared to the effects of Ruxolitinib.

  • Advantages: scleroderma phenotype translatable to humans, low mortality, flexible treatment window, well-published.
  • Disadvantages: variable disease penetrance and progression.
Model Systems
  • LP/J Mice (donor) à C57Bl/6 Mice (host)
Standard Readouts
  • Survival
  • Percent weight change
  • GVHD score (standard and modified)
  • Progression free survival
  • Plasma/serum cytokines
  • Terminal histopathology and/or IHC analyses
Additional Readouts
  • Engraftment assessment
  • Peripheral blood/lymphoid organ immunophenotyping
  • Custom assays
Representative DataClick Image to Enlarge
Percent Weight Change in the Murine Sclerodermatous Chronic GVHD Model

Recipient mice are pre-conditioned and transplanted with donor-derived bone marrow cells supplemented with splenocytes on Day 0. Animals are weighed daily, and body weight change as compared to Day 0 is calculated (top). To normalize for survivor bias, percent weight change with death weight carried forward is calculated (bottom). The AUC is calculated to compare treatment groups and is shown in the inset. (****: p<0.0001; compared to GVHD-Vehicle group)

GVHD score (standard) in the Murine Sclerodermatous Chronic GVHD Model

GVHD mice are assessed daily for weight loss, posture, activity, fur texture, and skin integrity phenotypes using our standard GVHD scoring scale. Each phenotype is scored and used to calculate the composite GVHD score (top). To normalize for survivor bias, GVHD score with death score carried forward is calculated (bottom). The AUC is calculated to compare treatment groups and is shown in the inset. (*: p<0.05; **: p<0.01 compared to GVHD-Vehicle group)

GVHD score in the Murine Sclerodermatous Chronic GVHD Model

GVHD mice are assessed daily for weight loss, posture, activity, fur texture, and skin integrity phenotypes using our Sclerodermatous Chronic GVHD scale. Each phenotype is scored and used to calculate the composite Sclerodermatous Chronic GVHD score (top). To normalize for survivor bias, Sclerodermatous Chronic GVHD score with death score carried forward is calculated (bottom). The AUC is calculated to compare treatment groups and is shown in the inset. (*: p<0.05; **: p<0.01 compared to GVHD-Vehicle group)

Survival in the Murine Sclerodermatous Chronic GVHD Model

Animals are assessed for survival and moribundity on a daily basis. (*: p<0.05 compared to GVHD-Vehicle group)

Progression Free Survival in the Murine Sclerodermatous Chronic GVHD Model

Progression free survival is tracked for the duration of the study and percent progression free survival is calculated for the standard GVHD scale (top) and the Sclerodermatous Chronic GVHD scale (bottom).

Representative photographs showing the development of sclerodermatous skin lesions over time in one animal.

Daniel Lichtman

Managing Partner