Development of intermediate-grade (mantle cell) and low-grade (small lymphocytic and marginal zone) human non-Hodgkin's lymphomas xenotransplanted in severe combined immunodeficiency mouse models.

We have used severe combined immunodeficiency (SCID) (c.b.-17, ICR/SCID) mice to develop xenotransplantation (XT) models for human intermediate-and-low-grade non-Hodgkin's lymphomas (NHL). In the past, SCID mice have provided a variety of useful XT models for human hematopoietic neoplasms that primarily involve the acute leukemias and some nonhematopoietic tumors, but only rare reports exist on use of the SCID mouse model in the study of primary tumor cells from NHL. Intermediate-grade and low-grade NHL are the most common lymphomas seen in adults. There is no effective therapy for those types of NHL, and they have not been established in an animal model to date. The lack of an animal model has hampered studies that can evaluate the disease process in vivo as well as the definition of therapeutic parameters involved in treatment. We report in this study that primary patient samples of NHL ( intermediate grade and low grade) have been successfully established in SCID mice after XT. NHL include intermediate-grade (mantle cell lymphoma) and low-grade (eg, small lymphocytic lymphoma/chronic lymphocytic lymphoma and marginal zone lymphoma) forms. Studies have been directed toward creating appropriate conditions for the optimal grafting of these NHL in SCID mice so that the disease process in humans could be accurately simulated. These studies indicate that development of XT-human lymphoma cells in SCID mice appear to be linked to their biologic and/or clinical behavior, transplanted lymphoma cell number, and age, as well as to the natural killer cell status of the SCID mouse recipients. Evidence has also shown that NHL cells can exhibit homing or trafficking patterns in SCID recipients that resemble those observed in patients with gastrointestinal lymphomatous involvement (particularly that of mantle cell lymphoma). Our studies also indicate that artefactual influences, such as the outgrowth of Epstein-Barr virus-associated lymphoblastoid lesions, are rare occurrences in the human NHL/SCID models that we have established.

Isolation and characterization of growth factor(s) from a human B-cell lymphoma.

We demonstrate that human neoplastic B cells (Br cells) contain a cytoplasmic protein of molecular mass 60 Kd that exhibits B-cell growth factor (BCGF) activity on growth factor-dependent long-term human B cells as well as on autochthonous tumor cells. This 60-Kd protein is recognized by antibodies against a similar intracellular 60-Kd protein derived from normal human lymphocytes. These results demonstrate that the two proteins share epitope homology. Microculture bioassays indicate that neoplastic and normal 60-Kd proteins are capable of driving neoplastic B cells through S-phase. Western immunoblot analysis indicates that neoplastic B cells secrete 60- as well as 14-Kd protein. Immunoaffinity-purified proteins secreted by Br cells exhibit BCGF activity in anti-IgM or dextran sulfate-preactivated human B cells. In addition, a double-antibody immunofluorescence staining technique was used to demonstrate that Br cells express cell surface receptors for BCGF molecule(s). These studies provide support for the autocrine growth model for neoplastic human B cells and suggest that the autocrine growth factor derived from such tumor cells is similar if not identical to normal BCGF molecules.

Growth factor-mediated tumor cell proliferation in hairy cell leukemia.

Leukemic B cells from seven patients with hairy cell leukemia (HCL), six of which contained the Tac antigen, were assayed in vitro for growth factor-mediated cell proliferation. The HCL cells showed typical phenotypic profiles by monoclonal antibody analysis. The tumor cells, which do not grow spontaneously in vitro, were found to proliferate in all but one case in response to partially purified B cell growth factor (BCGF) without anti-mu or Sac activation. Recombinant interleukin 2 however produced only a marginal response and could not support leukemic cell growth in vitro. BCGF, however, did stimulate in vitro cell growth and supported the establishment of continuous (greater than 60 d in vitro) in four of the seven HCL cases.