Inhibition of murine B and T lymphopoiesis in vivo by an anti-interleukin 7 monoclonal antibody.

Abstract

SummaryThe effects ofinterleukin 7 (IL-7) on the growth and differentiation of murine B cell p~ogenitors has been well characterized using in vitro culture methods. We have investigated the role of IL-7 in vivo using a monoclonal antibody that neutralizes IL-7. We find that treatment of mice with this antibody completely inhibits the development of B cell progenitors from the pro-B cell stage forward. We also provide evidence that all peripheral B cells, including those of the B-1 and conventional lineages, are derived from IL-7-dependent precursors. The results are consistent with the rapid turnover of B cell progenitors in the marrow, but a slow turnover of mature B cells in the periphery. In addition to effects on B cell development, anti-IL-7 treatment substantially reduced thymus cellularity, affecting all major thymic subpopulations. In the adult mouse, B lymphocytes develop from progenitor cells in the bone marrow. This development proceeds in an ordered fashion and can be characterized by the sequential acquisition of Ig gene rearrangements and cell surface markers (1, 2). The principal marker of the B lineage in murine bone marrow is the CD45R isoform identified by the 6B2 mAb and is designated B220 (3). The earliest cells committed to the B lineage, however, are B220-(4). A number of other cell surface antigens have been described whose expression is characteristic of particular stages in the sequence orb cell development (1) which culminates in the expression of functional surface IgM.The early development of B cells in the marrow is dependent on stromal cells and is mediated by cell contact and secreted cytokines (5). The role of cytokines in the development of B lymphocytes has been characterized primarily using in vitro methods in which particular cytokines such as IL-7 (6), mast cell growth factor (kit ligand) (7) or its antagonist (8), or insulin-like growth factor 1 (9) can be shown to regulate the proliferation of B cell progenitors. In vitro data suggest that as Ig genes rearrange, B cell progenitors progress from a stage in which they are stromal cell dependent and IL-7 independent to a stage in which they require IL-7 (10, 11). Very little information has been available on the actual role of these molecules in vivo, although treatment of normal mice with recombinant IL-7 has been shown to greatly augment B lymphopoiesis (12).The extent to which the B cells in the peripheral lymphoid organs are derived from IL-7-dependent precursors remains unclear. Whereas pre-B cells in the marrow turn over very rapidly, the rate at which cells turn over in the periphery appears to be much slower. This view is based on studies using bromodeoxyuridine administration (13) which indicate that the majority of peripheral B cells are long-lived. A small proportion of peripheral B cells turns over more rapidly and these are presumably replaced by newly developed marrowderived immature cells. B cells of the B-1 lineage, found primarily in the peritoneum, self-renew in the adult and are derived from immature progeni...

IL-4 Promotes Stat6-Dependent Survival of Autoreactive B Cells In Vivo Without Inducing Autoantibody Production

“…Ag-activated B cells. These studies used BrdU labeling to identify cells that had divided while BrdU was being administered (predominantly newly generated B cells) (33) and anti-IL-7 mAb to inhibit B lymphopoiesis in the bone marrow (28). An initial study, in which Ig Tgn and HEL-Ig mice were treated with BrdU Ϯ IL-4C Ϯ anti-IL-7 mAb for the 14 days before sacrifice (Fig.…”

Retroviral transduction of IL-7Rα into IL-7Rα−/− bone marrow progenitors: correction of lymphoid deficiency and induction of neutrophilia

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Relatively Normal Human Lymphopoiesis but Rapid Turnover of Newly Formed B Cells in Transplanted Nonobese Diabetic/SCID Mice

“…Gene targeting experiments and natural mutations suggest that IL-7 is more important for B cell formation in mice than it is in humans (1)(2)(3)(4). On the other hand, consequences of mutations in the Btk tyrosine kinase gene are more severe for humans than for mice (5,6).…”