Clinicopathologic Effects of Xenogeneic GvHD Induced by Adoptively Transferred Human-Derived T Cells in Severely Immunodeficient Mice.

BACKGROUND

Xenogeneic graft-versus-host disease (xGvHD) is an inevitable confounder of preclinical evaluation of adoptive immunotherapies on tumor-bearing immunodeficient mouse models. This study was designed to appraise the clinical and histopathological effects caused by xGvHD in severely immunodeficient mice considering the T cell dosage.

METHODS

Fifty NOG mice underwent intraperitoneal injection of three different doses of human-derived total T cells, a high dose of CD8T cells, or vehicle (as control). Clinical and histopathological status of the study subjects were evaluated and compared according to scoring systems.

RESULTS

In mice receiving higher doses of total T cells, the clinical severity of xGvHD was greater. However, recipients of CD8T cells developed none to mild xGvHD manifestations. Higher doses of T cells were associated with poorer outcomes including premature death and more severe histopathologic damages. Greater CD3T cell tissue engraftment (immunohistochemical CD3 positivity) was associated with more severe xGvHD-induced histopathological damages. Clinical xGvHD scores were significantly correlated with histopathological xGvHD scores in total and in each tissue. Mice with severe cutaneous symptoms had higher scores of xGvHD-induced histopathologic changes in the skin. Lethargy was associated with higher histopathological scores in the lungs, liver and spleen.

CONCLUSION

In preclinical evaluations, lower doses of T cell-based therapies are associated with milder xGvHD. Development of xGvHD may be averted by the use of CD4T cell-depleted grafts. Histopathological and clinical scoring systems for evaluating xGvHD are significantly correlated. The lungs and liver are reliable organs for histopathological assessment and scoring of xGvHD.