JAK3-deficient mini-pigs exhibit impaired lymphoid organogenesis, intestinal structure, and leukocyte/cytokine production

Abstract

Introduction: Severe combined immunodeficiency (SCID) mini-pigs are a highly versatile model for human disease research and regenerative medicine. Objectives: This study aims to generate a novel JAK3-deficient mini-pig model with a human-like immune system and to elucidate how JAK3 plays an important role in immune system. Methods: JAK3 and RAG2 knockout (KO) mini-pigs were generated using CRISPR/Cas9 and somatic cell nuclear transfer. These mini-pigs were transferred to a sterilized isolator within a specific pathogen-free facility. Phenotypic characteristics and clinical manifestations were analyzed through histological and hematological analysis of SCID mini-pigs to explore the unique role of JAK3 in immune functions. Results: JAK3 KO was characterized by defects in T and NK cells, very low levels of B cells, and a complete absence of thymus and lymph nodes. Notably, JAK3 KO mini-pigs had significantly reduced numbers of monocytes in peripheral blood, macrophages in tissue, and inflammatory cytokines, suggesting that JAK3 KO can induce a broad immunodeficiency that extends to the myeloid system as well as the lymphoid. Moreover, JAK3 KO mini-pigs had intestinal abnormalities similar to those of patients. Conclusion: These results suggest that JAK3 KO mini-pigs can be used as an effective model for the development of therapies for SCID patients, as well as for regenerative medicine applications such as the development of patient-specific artificial organs. © 2025 The Author(s)