Embodying AACAP's Presidential Initiative to Combat Digital Racism in Youth.

In her presidential initiative, AACAP President Dr. Tami Benton outlined her vision for the dynamic role of child and adolescent psychiatrists and their respective communities, encouraging them to transcend traditional clinical roles and become public health advocates by "Bringing the Village to the Children." This message emphasizes the capacity of child and adolescent psychiatrists to reach beyond clinical silos and identify partnerships across a variety of disciplines to improve child mental health.

CD83 Antibody Inhibits Human B Cell Responses to Antigen as well as Dendritic Cell-Mediated CD4 T Cell Responses.

Anti-CD83 Ab capable of Ab-dependent cellular cytotoxicity can deplete activated CD83 human dendritic cells, thereby inhibiting CD4 T cell-mediated acute graft-versus-host disease. As CD83 is also expressed on the surface of activated B lymphocytes, we hypothesized that anti-CD83 would also inhibit B cell responses to stimulation. We found that anti-CD83 inhibited total IgM and IgG production in vitro by allostimulated human PBMC.

GSK3 inhibition prevents lethal GVHD in mice.

Graft-versus-host disease (GVHD) is a major contributor to transplant-related mortality and morbidity after allogeneic stem cell transplantation. Despite advancements in tissue-typing techniques, conditioning regimens, and therapeutic intervention, the incidence rate of GVHD remains high. GVHD is caused by alloreactive donor T cells that infiltrate and destroy host tissues (e.

Unraveling the "known unknowns": lessons and reflections from the new directions in leukemia research 2012 conference.

Patients diagnosed with leukemia approach their treatment with the hope of cure despite the effect on their quality of life. Some patients will be cured, others will die from treatment, and some will die of their disease. A common theme at the New Directions in Leukemia Research (NDLR 2012) meeting was that cure will come if the drivers of the disease are better understood.

Comprehensive transcriptome and immunophenotype analysis of renal and cardiac MSC-like populations supports strong congruence with bone marrow MSC despite maintenance of distinct identities.

Cells resembling bone marrow mesenchymal stem cells (MSC) have been isolated from many organs but their functional relationships have not been thoroughly examined. Here we compared the immunophenotype, gene expression, multipotency and immunosuppressive potential of MSC-like colony-forming cells from adult murine bone marrow (bmMSC), kidney (kCFU-F) and heart (cCFU-F), cultured under uniform conditions. All populations showed classic MSC morphology and in vitro mesodermal multipotency.

Micromarrows--three-dimensional coculture of hematopoietic stem cells and mesenchymal stromal cells.

Hematopoietic stem cell (HSC) transplant is a well established curative therapy for some hematological malignancies. However, achieving adequate supply of HSC from some donor tissues can limit both its application and ultimate efficacy. The theory that this limitation could be overcome by expanding the HSC population before transplantation has motivated numerous laboratories to develop ex vivo expansion processes.

Mobilisation strategies for normal and malignant cells.

This review evaluates the latest information on the mobilisation of haemopoietic stem cells for transplantation, with the focus on what is the current best practice and how new understanding of the bone marrow stem cell niche provides new insights into optimising mobilisation regimens. The review then looks at the mobilisation of mesenchymal stromal cells, immune cells as well as malignant cells and what clinical implications there are.

Myeloma-induced alloreactive T cells arising in myeloma-infiltrated bones include double-positive CD8+CD4+ T cells: evidence from myeloma-bearing mouse model.

The graft-versus-myeloma (GVM) effect represents a powerful form of immune attack exerted by alloreactive T cells against multiple myeloma cells, which leads to clinical responses in multiple myeloma transplant recipients. Whether myeloma cells are themselves able to induce alloreactive T cells capable of the GVM effect is not defined. Using adoptive transfer of T naive cells into myeloma-bearing mice (established by transplantation of human RPMI8226-TGL myeloma cells into CD122(+) cell-depleted NOD/SCID hosts), we found that myeloma cells induced alloreactive T cells that suppressed myeloma growth and prolonged survival of T cell recipients.

CD34+ cord blood DC-induced antitumor lymphoid cells have efficacy in a murine xenograft model of human ALL.

Acute lymphocytic leukemia (ALL) patients who relapse after transplantation have few therapeutic options. An immunotherapeutic approach that enhances the graft versus leukemia effect may improve their survival. We postulate that cytotoxic T lymphocytes (CTLs) generated from total RNA loaded cord blood CD34+-derived dendritic cells can control the kinetics of leukemic growth in a nonobese diabetic/severe combined immunodeficient (NOD-SCID) mouse model of human ALL.

Mesenchymal stromal cells transiently alter the inflammatory milieu post-transplant to delay graft-versus-host disease.

Background: Multipotent mesenchymal stromal cells suppress T-cell function in vitro, a property that has underpinned their use in treating clinical steroid-refractory graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. However the potential of mesenchymal stromal cells to resolve graft-versus-host disease is confounded by a paucity of pre-clinical data delineating their immunomodulatory effects in vivo.

Design And Methods: We examined the influence of timing and dose of donor-derived mesenchymal stromal cells on the kinetics of graft-versus-host disease in two murine models of graft-versus-host disease (major histocompatibility complex-mismatched: UBI-GFP/BL6 [H-2(b)]→BALB/c [H-2(d)] and the sibling transplant mimic, UBI-GFP/BL6 [H-2(b)]→BALB.

Reduced intensity conditioning for hematopoietic stem cell transplantation: has it achieved all it set out to?

At its inception, reduced intensity conditioning (RIC) was heralded as a means to limit toxicity after hematopoietic stem cell transplantation (HSCT), especially for the older patient demographic. The aim was to promote the inherent anti-leukemic activity of the transplant whilst reducing toxicity and transplant-related mortality (TRM). More than 10 years on, much has been learnt about the role of conditioning in determining outcomes after transplantation.

Antibody to the dendritic cell surface activation antigen CD83 prevents acute graft-versus-host disease.

Allogeneic (allo) hematopoietic stem cell transplantation is an effective therapy for hematological malignancies but it is limited by acute graft-versus-host disease (GVHD). Dendritic cells (DC) play a major role in the allo T cell stimulation causing GVHD. Current immunosuppressive measures to control GVHD target T cells but compromise posttransplant immunity in the patient, particularly to cytomegalovirus (CMV) and residual malignant cells.

Reduced intensity conditioning for allogeneic hematopoietic stem-cell transplant determines the kinetics of acute graft-versus-host disease.

Background: Preparative myeloablative conditioning regimens for allogeneic hematopoietic stem-cell transplantation (HSCT) may control malignancy and facilitate engraftment but also contribute to transplant related mortality, cytokine release, and acute graft-versus-host disease (GVHD). Reduced intensity conditioning (RIC) regimens have decreased transplant related mortality but the incidence of acute GVHD, while delayed, remains unchanged. There are currently no in vivo allogeneic models of RIC HSCT, limiting studies into the mechanism behind RIC-associated GVHD.

Compartmentalization of allogeneic T-cell responses in the bone marrow and spleen of humanized NOD/SCID mice containing activated human resident myeloid dendritic cells.

Objective: Human allogeneic (allo)-T-cell responses within recipient lymphoid tissues and the degree to which they are altered in the presence of activated tissue-resident dendritic cells (DC) remain unknown. This study examined allo-T-cell recruitment and the early allo-T-cell responses that occur in the bone marrow (BM) and spleen (SP) of humanized (hu) nonobese diabetic (NOD)/severe combined immunodeficient (SCID) recipients containing activated human tissue-resident myeloid DC (MDC).

Materials And Methods: Human naïve allo-T cells were transferred into polyinosinic:polycytidylic acid [poly(I:C)]-treated or untreated huNOD/SCID recipients containing human tissue-resident DC derived from transplanted CD34(+) cells.

Therapeutic applications of mesenchymal stromal cells.

Mesenchymal stromal cells (MSC) are multipotent cells that can be derived from many different organs and tissues. They have been demonstrated to play a role in tissue repair and regeneration in both preclinical and clinical studies. They also have remarkable immunosuppressive properties.

RNA loading of leukemic antigens into cord blood-derived dendritic cells for immunotherapy.

The manipulation of dendritic cells (DCs) ex vivo to present tumor-associated antigens for the activation and expansion of tumor-specific cytotoxic T lymphocytes (CTLs) attempts to exploit these cells' pivotal role in immunity. However, significant improvements are needed if this approach is to have wider clinical application. We optimized a gene delivery protocol via electroporation for cord blood (CB) CD34(+) DCs using in vitro-transcribed (IVT) mRNA.

Mutant N-ras preferentially drives human CD34+ hematopoietic progenitor cells into myeloid differentiation and proliferation both in vitro and in the NOD/SCID mouse.

Objectives: Ras oncogene mutations are the most frequently observed genetic abnormality (20-40% of patients) in acute myeloid leukemia (AML), and in the preleukemic conditions myelodysplastic syndrome (MDS) and myeloproliferative disorder (MPD). We have previously shown that mutant N-ras (N-rasm) can induce myeloproliferative disorders and apoptosis in a murine reconstitution system. In the present study we investigated the effect of N-rasm in human primary hematopoietic progenitor cells (HPC).

Characterization of childhood acute lymphoblastic leukemia xenograft models for the preclinical evaluation of new therapies.

Continuous xenografts from 10 children with acute lymphoblastic leukemia (ALL) were established in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Relative to primary engrafted cells, negligible changes in growth rates and immunophenotype were observed at second and third passage. Analysis of clonal antigen receptor gene rearrangements in 2 xenografts from patients at diagnosis showed that the pattern of clonal variation observed following tertiary transplantation in mice exactly reflected that in bone marrow samples at the time of clinical relapse.

Technology evaluation: APC-80200, Dendreon.

APC-80200 (Mylovenge) has been developed for the treatment of B-cell malignancies and is currently in phase II clinical trials as a therapeutic vaccine for patients with advanced multiple myeloma. This vaccine candidate appears to be of particular benefit in patients who have received high-dose chemotherapy to reduce tumor load following stem cell rescue. APC-80200 is also being tested in patients with amyloidosis.

The nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse model of childhood acute lymphoblastic leukemia reveals intrinsic differences in biologic characteristics at diagnosis and relapse.

Acute lymphoblastic leukemia cells from 19 children, including 7 who remain in first complete remission (CR1), were engrafted into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. High-level infiltration of bone marrow, spleen, and liver was observed, with variable infiltration of other organs. The immunophenotypes of xenografts were essentially unaltered compared with the original patient sample.