Spontaneous xenogeneic GvHD in Wilms' tumor Patient‐Derived xenograft models and potential solutions

• Published in: Animal models and experimental medicine 2022-12, Vol.5 (4), p.389-396
• Main Authors: Monzavi, Seyed Mostafa, Muhammadnejad, Ahad, Behfar, Maryam, Khorsand, Amir Arsalan, Muhammadnejad, Samad, Kajbafzadeh, Abdol‐Mohammad
• Format: Article
• Language: English
• Subjects: Adenoviruses; Amputation; Body weight loss; CD3 antigen; CD8 antigen; Dermatitis; Erythema; Graft-versus-host reaction; graft‐versus‐host disease; Hair; Hepatitis; Immunodeficiency; Inflammation; Lymphadenopathy; Lymphatic system; Lymphocytes; Mutation; Pathology; Patients; patient‐derived xenograft models; Pneumonitis; Regular; Short Communication; Solid tumors; Transplantation; tumor‐infiltrating lymphocytes; Wilms' tumor; Xenografts
• ISSN: 2576-2095; 2096-5451; 2576-2095
• DOI: 10.1002/ame2.12254

Severely immunocompromised NOD.Cg‐PrkdcscidIl2rgtm1Sug (NOG) mice are among the ideal animal recipients for generation of human cancer models. Transplantation of human solid tumors having abundant tumor‐infiltrating lymphocytes (TILs) can induce xenogeneic graft‐versus‐host disease (xGvHD) following engraftment and expansion of the TILs inside the animal body. Wilms' tumor (WT) has not been recognized as a lymphocyte‐predominant tumor. However, 3 consecutive generations of NOG mice bearing WT patient‐derived xenografts (PDX) xenotransplanted from a single donor showed different degrees of inflammatory symptoms after transplantation before any therapeutic intervention. In the initial generation, dermatitis, auto‐amputation of digits, weight loss, lymphadenopathy, hepatitis, and interstitial pneumonitis were observed. Despite antibiotic treatment, no response was noticed, and thus the animals were prematurely euthanized (day 47 posttransplantation). Laboratory and histopathologic evaluations revealed lymphoid infiltrates positively immunostained with anti‐human CD3 and CD8 antibodies in the xenografts and primary tumor, whereas no microbial infection or lymphoproliferative disorder was found. Mice of the next generation that lived longer (91 days) developed sclerotic skin changes and more severe pneumonitis. Cutaneous symptoms were milder in the last generation. The xenografts of the last 2 generations also contained TILs, and lacked lymphoproliferative transformation. The systemic immunoinflammatory syndrome in the absence of microbial infection and posttransplant lymphoproliferative disorder was suggestive of xGvHD. While there are few reports of xGvHD in severely immunodeficient mice xenotransplanted from lymphodominant tumor xenografts, this report for the first time documented serial xGvHD in consecutive passages of WT PDX‐bearing models and discussed potential solutions to prevent such an undesired complication. Three consecutive generations of NOG mice bearing Wilms tumor patient‐derived xenografts from a single donor showed different degrees of immunoinflammatory symptoms. Histopathologic evaluations of the xenografts and parental tumor showed lymphoid infiltrates and human‐originated CD3 and CD8 positive cells in the tissue blocks, while no lymphoproliferative disorder was evident (suggestive of a lymphodominant tumor graft). In the absence of microbial infection and lymphoproliferative disorder, the syndrome was suggestive of xenogeneic graft‐versu