Xenotransplantation of human lymphoid malignancies is optimized in mice with multiple immunologic defects

Abstract

While it is known that mice with genetic immune defects are useful for establishing durable engraftment of human tumor xenografts, the relative role of components of host innate and adoptive immunity in engraftment has not been determined. We directly compared the ability of four strains of genetically immunodeficient mice (NOD/SCID, SCID, Nude and Rag-1-deficient) to successfully engraft and support the human cell lines Daudi, Raji, Namalwa and Molt-4 as subcutaneous tumors. We additionally examined the effect of further immunosuppression of the mice by whole body irradiation at a dose of 600 cGy for Nude and Rag-1 and 300 cGy for SCID mice and by administration of anti-natural killer (asialo-GM1) antibody on tumor growth. Mice with each of the defects supported xenografts to varying degrees. We found differences in growth characteristics in the cell lines tested, with Namalwa consistently producing the largest tumors. With all cell lines studied, optimal growth was achieved using NOD/SCID mice. Overall, tumor growth was somewhat enhanced by pretreatment with radiation with little additional benefit from the addition of anti-asialo-GM1 antibody. The importance of multiple components of the innate and adoptive immune system in xenotransplantation were best demonstrated when results in untreated NOD/SCID mice were compared to SCID, nude and RAG-1-deficient mice. The NOD/SCID mouse with or without additional immunosuppression provides the optimal model for the study of the biology and treatment of human leukemias and lymphomas.

Ly-49P Activates NK-Mediated Lysis by Recognizing H-2Dd 1

“…The NOD/SCID mouse has shown particular utility in studying human tumor growth and development as well as human hemopoiesis, since it accepts a broader spectrum of human xenografts than SCID or nude mice (59,63). Human graft acceptance by NOD/SCID mice has been suggested to be due to the NK functional deficiency of the NOD mouse in combination with a lack of B cells and T cells related to the SCID mutation (59,63).…”

“…Human graft acceptance by NOD/SCID mice has been suggested to be due to the NK functional deficiency of the NOD mouse in combination with a lack of B cells and T cells related to the SCID mutation (59,63). Mice lacking the common ␥-chain, which is required for signaling through a number of cytokine receptors, including IL-2R and IL-15R, do not develop functional NK cells (64).…”

A Nod Scid mouse model to study human prostate cancer

“…A comparative study of tumor growth rate of various hematopoietic cancer cell lines in different animal models (Nude, Rag1, Scid and Nod Scid mice) has shown a better growth rate in the Nod Scid model. 11 To our knowledge, the Nod Scid mouse has been used once as a preclinical model for prostate cancer but without orthotopic implantation. 12 In the present study, the Nod Scid mouse has been used for subcutaneous and orthotopic implantation of human prostate carcinoma cell lines in order to validate a new relevant model for gene therapy studies and to link therapeutic efficiency with transgen expression without implying the own animal immunity.…”

Inhibition of angiogenesis and induction of endothelial and tumor cell apoptosis by green tea in animal models of human high-grade non-Hodgkin's lymphoma

“…Taking advantage of the enhanced immunosuppression of NOD/SCID mice compared to other strains, 12 we have generated reliable in vivo models of aggressive i.p. human B cell NHLs which are measurable, more similar to the human disease and have 100% engraftment efficiency.…”

“…Although mice bearing the Nude or the SCID mutation have been extensively used to evaluate human malignancies in vivo, these strains have residual immunity that may limit post-transplant neoplastic cell growth, while the NOD/SCID strain appears to be more convenient for human leukemia/lymphoma xenotransplantation. 12 In our study, mice were transplanted intraperitoneally (i.p.) instead of subcutaneously (s.c.) to generate a disease more similar to human B cell NHL.…”