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

• Published in: Archives of Iranian medicine Vol. 27; no. 12; pp. 683 - 692
• Main Authors: Ashraf, Hami, Kosari, Farid, Khorsand, Amir Arsalan, Muhammadnejad, Samad, Mansouri, Vahid, Muhammadnejad, Ahad, Ahmadbeigi, Naser, Monzavi, Seyed Mostafa
• Format: Journal Article
• Language: English
• Published: Iran Academy of Medical Sciences of I.R. Iran 01.12.2024
• Subjects: Adoptive Transfer; Animals; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - transplantation; Disease Models, Animal; Female; Graft vs Host Disease - immunology; Graft vs Host Disease - pathology; Humans; Lymphocytes; Mice; Mice, SCID; Original; T-Lymphocytes - immunology; T-Lymphocytes - transplantation; Evaluation; Host disease; Xenotransplantation; Adoptive immunotherapy; Graft; Immunodeficient mice; Preclinical drug
• ISSN: 1029-2977; 1735-3947
• DOI: 10.34172/aim.28597

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 CD8+T 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 CD8+T 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 CD3+T 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 CD4+T 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.