Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer.

Two major populations of myeloid-derived suppressor cells (MDSCs), monocytic MDSCs (M-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs) regulate immune responses in cancer and other pathologic conditions. Under physiologic conditions, Ly6C(hi)Ly6G(-) inflammatory monocytes, which are the normal counterpart of M-MDSCs, differentiate into macrophages and dendritic cells. PMN-MDSCs are the predominant group of MDSCs that accumulates in cancer. Here we show that a large proportion of M-MDSCs in tumor-bearing mice acquired phenotypic, morphological and functional features of PMN-MDSCs. Acquisition of this phenotype, but not the functional attributes of PMN-MDSCs, was mediated by transcriptional silencing of the retinoblastoma gene through epigenetic modifications mediated by histone deacetylase 2 (HDAC-2). These data demonstrate a new regulatory mechanism of myeloid cells in cancer.

Lineage extrinsic and intrinsic control of immunoregulatory cell numbers by SHIP.

We previously showed that germline or induced SHIP deficiency expands immuno-regulatory cell numbers in T lymphoid and myeloid lineages. We postulated these increases could be interrelated. Here, we show that myeloid-specific ablation of SHIP leads to the expansion of both myeloid-derived suppressor cell (MDSC) and regulatory T (Treg) cell numbers, indicating SHIP-dependent control of Treg-cell numbers by a myeloid cell type. Conversely, T-lineage specific ablation of SHIP leads to expansion of Treg-cell numbers, but not expansion of the MDSC compartment, indicating SHIP also has a lineage intrinsic role in limiting Treg-cell numbers. However, the SHIP-deficient myeloid cell that promotes MDSC and Treg-cell expansion is not an MDSC as they lack SHIP protein expression. Thus, regulation of MDSC numbers in vivo must be controlled in a cell-extrinsic fashion by another myeloid cell type. We had previously shown that G-CSF levels are profoundly increased in SHIP(-/-) mice, suggesting this myelopoietic growth factor could promote MDSC expansion in a cell-extrinsic fashion. Consistent with this hypothesis, we find that G-CSF is required for expansion of the MDSC splenic compartment in mice rendered SHIP-deficient as adults. Thus, SHIP controls MDSC numbers, in part, by limiting production of the myelopoietic growth factor G-CSF.

SHIP limits immunoregulatory capacity in the T-cell compartment.

Regulatory T cells (T(regs)) play a pivotal role in preventing autoimmunity, graft-versus-host disease (GVHD), and organ graft rejection. We previously showed that either germline or induced SH2 domain-containing inositol 5-phosphatase (SHIP) deficiency in the host abrogates GVHD. Here we show that SHIP deficiency promotes an increase of CD4(+)CD25(+)FoxP3(+) T(regs) and CD4(+)CD25(-)FoxP3(+)"naive" T cells in the periphery that display increased CD103, glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR), OX40, and FcgammaRII/III expression. SHIP deficiency does not compromise T(reg) function because SHIP-deficient CD3(+)CD4(+)CD25(+) T(regs) are as suppressive as wild-type (WT) CD3(+)CD4(+)CD25(+) T(reg). Interestingly, like conventional T(regs), SHIP(-/-) CD4(+)CD25(-) T cells are unresponsive to major histocompatibility complex (MHC)-mismatched stimulators and suppress allogeneic responses by T cells in vitro. In addition, SHIP(-/-) CD4(+)CD25(-) T cells mediate reduced lethal GVHD on adoptive transfer to MHC-mismatched hosts. Furthermore, hosts with induced SHIP deficiency exhibit delayed rejection of MHC-mismatched cardiac grafts. Thus, SHIP is required for robust graft-versus-host and host-versus-graft responses by CD4(+) T cell and limits their immunoregulatory capacity. These findings further define the immunosuppressive mechanisms that result from SHIP deficiency and provide additional justification for targeting SHIP in clinical transplantation.

Subsets of myeloid-derived suppressor cells in tumor-bearing mice.

Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of cells that play a critical role in tumor associated immune suppression. In an attempt to identify a specific subset of MDSC primarily responsible for immunosuppressive features of these cells, 10 different tumor models were investigated. All models showed variable but significant increase in the population of MDSC. Variability of MDSC expansion in vivo matched closely the effect of tumor cell condition medium in vitro. MDSC consists of two major subsets of Ly6G(+)Ly6C(low) granulocytic and Ly6G(-)Ly6C(high) monocytic cells. Granulocytic MDSC have increased level of reactive oxygen species and undetectable level of NO whereas monocytic MDSC had increased level of NO but undetectable levels of reactive oxygen species. However, their suppressive activity per cell basis was comparable. Almost all tumor models demonstrated a preferential expansion of granulocytic subset of MDSC. We performed a phenotypical and functional analysis of several surface molecules previously suggested to be involved in MDSC-mediated suppression of T cells: CD115, CD124, CD80, PD-L1, and PD-L2. Although substantial proportion of MDSC expressed those molecules no differences in the level of their expression or the proportion, positive cells were found between MDSC and cells from tumor-free mice that lack immune suppressive activity. The level of MDSC-mediated T cell suppression did not depend on the expression of these molecules. These data indicate that suppressive features of MDSC is caused not by expansion of a specific subset but more likely represent a functional state of these cells.

Prevalence of contact allergens in a Hispanic population.

BACKGROUND: Patch testing has been used as a screening tool to identify those allergens responsible for the development of allergic contact dermatitis. The objectives of this study were to identify the most common allergens found at the Patch Testing Clinic (PTC) of the Department of Dermatology, Medical Sciences Campus (MSC) University of Puerto Rico (UPR), to correlate patch testing results with demographics and clinical data, and to compare the results with similar studies in other institutions. METHODS: A retrospective analysis of the records of patients who underwent patch testing for suspected acute allergic contact dermatitis at the Department of Dermatology of the Medical Sciences Campus of the UPR, from March 31, 2001 to May 31, 2005. Information regarding demographics, medical history, occupation, and test results was retrieved. RESULTS: The most common allergens identified were: carba mix, nickel sulphate, thiuram mix, paratertiary butylphenol formaldehyde resin, paraphenylenediamine, and neomycin sulphate. The most commonly affected area was the hands. A correlation was observed between paratertiary butylphenol and involvement of the feet, paraphenylenediamine and generalized dermatitis, and potassium dichromate and occupational exposure. CONCLUSIONS: Patch testing remains a worthwhile and quick diagnostic tool for the evaluation of patients with suspected allergic contact dermatitis.

Etanercept therapy for psoriasis in a patient with concomitant hepatitis C and liver transplant.

We report a case of a 49 year-old male who had undergone liver transplant due to hepatitis C, Laennec's cirrhosis, and hepatocellular carcinoma, and was treated with etanercept for recalcitrant generalized psoriasis. Clearance of psoriasis was achieved without any adverse effects or complications of his current conditions.

Characterization of the nature of granulocytic myeloid-derived suppressor cells in tumor-bearing mice.

MDSCs are a group of cells with potent immune-suppressive activity. These cells accumulate in many pathologic conditions and play a major role in the regulation of immune responses. The nature of MDSC remains highly debatable. In cancer, most MDSCs are represented by cells with granulocytic phenotype and morphology, G-MDSC. The relationship between G-MDSCs and Neu remains unclear. In this study, we have found that G-MDSCs, from tumor-bearing, and Neu, from tumor-free, mice share a common morphology and phenotype. However, in contrast to Neu, a substantial proportion of G-MDSCs expressed M-CSFR and a CD244 molecule. Neu had significantly higher phagocytic activity, expression of lysosomal proteins, and TNF-α than corresponding G-MDSCs, which had significantly higher activity of arginase, MPO, and ROS. In contrast to G-MDSC, neither rested nor mobilized Neu suppressed T cells. G-MDSC survived 2 days in culture in the presence of GM-CSF and within 24 h, became phenotypic and functionally similar to Neu. Tumor-associated G-MDSC shared most characteristics of splenic G-MDSC, rather then Neu. These data suggest that in cancer, despite morphological and phenotypic similarities, G-MDSCs are functionally distinct from Neu and are comprised of pathologically activated precursors of Neu.