The Role of Regulatory B Cell-Like Malignant Cells and Treg Cells in the Mouse Model of BCL1 Tumor Dormancy.

Cancer dormancy is a clinical state in which residual tumor cells persist for long periods of time but do not cause detectable disease. In the mouse B cell lymphoma model (BCL1), dormancy can be induced and maintained by immunizing mice with a soluble form of the IgM expressed on the surface of the tumor cells. Immunization induces an anti-idiotype antibody response that maintains dormancy.

Partial depletion of regulatory T cells does not influence the inflammation caused by high dose hemi-body irradiation.

There is clinical interest in the modulation of regulatory T cells for cancer therapy. The safety of these therapies in combination with conventional anti-cancer therapies, including radiation therapy, can be studied in animal models. The effects of partial depletion of regulatory T (Treg) cells with an anti-CD25 antibody in conjunction with ionizing radiation on inflammation and tissue injury were analyzed in C57BL/6 mice.

25-Hydroxycholesterol secreted by macrophages in response to Toll-like receptor activation suppresses immunoglobulin A production.

25-Hydroxycholesterol is produced in mammalian tissues. The function of this oxysterol is unknown. Here we describe a central role for 25-hydroxycholesterol in regulating the immune system.

Protection against lethal Aspergillus fumigatus infection in mice by allogeneic myeloid progenitors is not major histocompatibility complex restricted.

Invasive fungal infections are a leading cause of morbidity and mortality after myelotoxic chemotherapy or radiation exposure. The resulting depletion of myeloid precursors under these conditions appears to be the factor that limits approaches to accelerate immune reconstitution. In a murine model of myeloablation after radiation exposure, we demonstrated that highly purified common myeloid and granulocyte-monocyte progenitors (CMPs/GMPs) accelerated myeloid recovery and, thus, enhanced innate immunity as measured by survival after a lethal challenge with Aspergillus fumigatus.

Stepwise development of committed progenitors in the bone marrow that generate functional T cells in the absence of the thymus.

We identified committed T cell progenitors (CTPs) in the mouse bone marrow that have not rearranged the TCRbeta gene; express a variety of genes associated with commitment to the T cell lineage, including GATA-3, T cell-specific factor-1, Cbeta, and Id2; and show a surface marker pattern (CD44+ CD25- CD24+ CD5-) that is similar to the earliest T cell progenitors in the thymus. More mature committed intermediate progenitors in the marrow have rearranged the TCR gene loci, express Valpha and Vbeta genes as well as CD3epsilon, but do not express surface TCR or CD3 receptors. CTPs, but not progenitors from the thymus, reconstituted the alphabeta T cells in the lymphoid tissues of athymic nu/nu mice.

Cytomegalovirus MCK-2 controls mobilization and recruitment of myeloid progenitor cells to facilitate dissemination.

Murine cytomegalovirus encodes a secreted, pro-inflammatory chemokine-like protein, MCK-2, that recruits leukocytes and facilitates viral dissemination. We have shown that MCK-2-enhanced recruitment of myelomonocytic leukocytes with an immature phenotype occurs early during infection and is associated with efficient viral dissemination. Expression of MCK-2 drives the mobilization of a population of leukocytes from bone marrow that express myeloid marker Mac-1 (CD11b), intermediate levels of Gr-1 (Ly6 G/C), platelet-endothelial-cell adhesion molecule-1 (PECAM-1, CD31), together with heterogeneous levels of stem-cell antigen-1 (Sca-1, Ly-6 A /E).

Single infusion of myeloid progenitors reduces death from Aspergillus fumigatus following chemotherapy-induced neutropenia.

Hematopoietic progenitors committed to the myeloid lineage, the common myeloid and granulocyte-monocyte progenitors (CMP/GMP), have been shown to protect against opportunistic pathogens following myeloablative radiation; however, the efficacy of this approach has not been studied in the setting of chemotherapy-induced neutropenia. In this mouse model, the infusion of CMP/GMP on the day after 5-fluorouracil (5-FU) administration (D+1) resulted in a significant increase in the number of splenic neutrophils by D+8 when compared with 5-FU-only controls (P = .02), the majority of which were CMP/GMP-derived (54%).

Common lymphoid progenitors rapidly engraft and protect against lethal murine cytomegalovirus infection after hematopoietic stem cell transplantation.

Lymphoid deficiency after allogeneic hematopoietic cell transplantation (HCT) results in increased susceptibility to infection; however, transplantation of mature lymphocytes frequently results in a serious complication known as graft-versus-host disease (GVHD). Here we demonstrate in mice that both congenic as well as allogeneic transplantation of low numbers of highly purified common lymphoid progenitors (CLPs)-a rare population of lymphoid-lineage-committed bone marrow cells-accelerates immune reconstitution after lethal irradiation and rescue with hematopoietic stem cells (HSCs). After congenic transplantation, 3 x 10(3) CLPs protected against murine cytomegalovirus (MCMV) infection at a level roughly equivalent to 107 unfractionated lymph node cells.

Myeloid progenitors protect against invasive aspergillosis and Pseudomonas aeruginosa infection following hematopoietic stem cell transplantation.

Myelotoxic treatments for oncologic diseases are often complicated by neutropenia, which renders patients susceptible to potentially lethal infections. In these studies of murine hematopoietic stem cell transplantation (HSCT), cotransplantation of lineage-restricted progenitors known as common myeloid progenitors (CMP) and granulocyte-monocyte progenitors (GMP) protects against death following otherwise lethal challenge with either of 2 pathogens associated with neutropenia: Aspergillus fumigatus and Pseudomonas aeruginosa. Cotransplantation of CMP/GMP resulted in a significant and rapid increase in the absolute number of myeloid cells in the spleen, most of which were derived from the donor CMP/GMP.

Prophylactic administration of liposomal amphotericin B is superior to treatment in a murine model of invasive aspergillosis after hematopoietic cell transplantation.

With use of a novel model of invasive Aspergillus fumigatus, the efficacy of prophylactic versus therapeutic administration of liposomal amphotericin B (L-AmB) was tested in C57BL/6 mice. After lethal irradiation and transplantation of whole bone marrow (d 0), animals were challenged with conidia either intravenously or via nasal instillation on d +3 and divided into 3 groups: group I received 5% dextrose in water throughout the study period; group II received L-AmB, 5 mg/kg, beginning on d +4; and group III received L-AmB, 5 mg/kg on d -4, d -2, d 0, and d +2, then daily starting d +4. Groups I and II did not survive intravenous challenge, whereas group III had a 40% survival rate.