A Model for Human B-Chronic Lymphocytic Leukemia in Human/Mouse Radiation Chimera: Evidence for Tumor-Mediated Suppression of Antibody Production in Low-Stage Disease

Abstract

B-chronic lymphocytic leukemia (BCLL) is a lymphoproliferative disease that is characterized by clonal expansion of CD5+ B cells. BCLL is associated with secondary immunodeficiency and hypogammaglobulinemia. It has been suggested that T-cell dysregulation may play a role in the hypogammaglobulinemia and in the increased incidence of autoimmunity in BCLL patients. We attempted to transfer human peripheral blood mononuclear cells (PBMC) from BCLL patients in different stages of the disease into immunodeficient mice. PBMC from BCLL patients in stage 0, stages I to II, and stages III to IV were transplanted into the peritoneal cavity of lethally irradiated Balb/c or beige/nude/Xid (BNX) mice radioprotected with bone marrow (BM) from severe combined immunodeficiency (SCID) mice. Different engraftment profiles were found in the chimeric mice 2 weeks after transplantation of PBMC according to the disease stage of the BCLL donors. Infusion of PBMC from donors in stage 0 led to marked engraftment of human T cells, whereas the human tumor cells could hardly be detected. In contrast, chimeric mice receiving PBMC from patients in stage III to IV disease exhibited engraftment with a dominance of tumor cells, compared with a miniscule level of T cells. The ability of the engrafted cells to produce human Ig was also found to be correlated with the disease stage of the donor, although all donors had the same magnitude of hypogammaglobulinemia. Total human Ig production in the chimeric mice was normal in mice receiving PBMC from donors in stage 0, whereas in chimeric mice engrafted with PBMC from donors in stages III to IV almost no human Igs could be detected. This differential reconstitution of antibody production in the mouse model according to the stage of the patient's disease will allow further studies on possible cellular interactions between malignant and immune cells in BCLL.

SCID Mouse Models of Human Stem Cell Engraftment

“…Soon after the discovery of scid mice, it was shown that lethally irradiated normal (immunocompetent) mice transplanted with C.B-17-scid marrow, followed later by a large dose of human bone marrow, resulted in low levels of human cell engraftment [41]. This model has been used to study human stem cell phenotype and differentiation [41], as well as the growth of human leukemias and lymphomas in vivo [64]. However, in these irradiated, scid marrow-engrafted, human marrow-injected mice, the role of natural antibodies derived from the irradiated immunocompetent host remains a potential obstacle [65].…”

Optimized Xenograft Protocol for Chronic Lymphocytic Leukemia Results in High Engraftment Efficiency for All CLL Subgroups

“…Most CLL xenograft mouse models so far use conditioning regimens like irradiation or chemotherapy to prime the mice before CLL injection, with the consequence of destroying or at least changing the hematopoietic stem cell niche and the microenvironment in primary and secondary lymphoid organs [24,31]. Furthermore allograft settings were introduced to improve the CLL engraftment by adding allogeneic CD34+ cord blood cells and antigen presenting allogeneic CD14+ monocytes or CD19+ B cells, with the consequence of unforeseeable immunological changes in CLL biology [27].…”

“…To circumvent such implications on the microenvironment and the immune system, we intended to develop a CLL xenograft protocol without any conditioning regimens. Furthermore, we aimed to focus on early stage, and good prognosis CLL samples, as they are underrepresented in the previous studies despite their frequent occurrence [24,31].…”

“…Previous publications have shown huge advantages in CLL cell engraftment for late stage CLLs (Rai stage III/IV) [23,24,31] and CLL subsets with poor prognosis [21], but at least half of the patients seen in the clinic present with genetic and expression features of good prognosis and early stage CLL. Furthermore, many xenograft models rely on complicated conditioning regimens (chemotherapy, irradiation) or allogeneic settings.…”

Effects of human interleukin‐18 and interleukin‐12 treatment on human lymphocyte engraftment in NOD‐scid mouse

“…In the past few years, NOD/LtSz-prkdc scid /prkdc scid (non-obese diabetic-severe combine immunodeficiency; NOD-scid) mice grafted with human peripheral blood lymphoid cells (PBLs) have been used as in vivo models for studying transplantation of haematolymphoid cells, human tumour biology, and humanspecific infection agents such as human immunodeficiency virus (HIV). [1][2][3][4] This mouse strain supports levels of human cell grafting that are five-to 10-fold greater than those obtained in C.B-17-scid mice. 5 As a result, the human PBL-NOD-scid model is employed for long-term in vivo analysis of immunoregulatory interactions between human lymphocyte activation and pathogens such as HIV.…”