The Southeastern U.S. Collaborative Center of Excellence in the Elimination of Disparities (SUCCEED): reducing breast and cervical cancer disparities for African American women.

This supplement highlights the efforts of Morehouse School of Medicine's Prevention Research Center and its partners to reduce the disparities experienced by African American women for breast and cervical cancer in Georgia, North Carolina and South Carolina. The project (entitled the Southeastern U.S. Collaborative CEED, or SUCCEED) is supported by a Centers for Disease Control and Prevention (CDC) grant to establish a Center of Excellence in the Elimination of Disparities (CEED). This introductory paper provides an overview describing the project's goals and core components and closes by introducing the adjoining papers that describe in more detail these components. The program components for SUCCEED include providing training and technical assistance for implementing evidence-based interventions for breast and cervical cancer; supporting capacity-building and sustainability efforts for community-based organizations; promoting the establishment of new empowered community coalitions and providing advocacy training to cancer advocates in order to affect health systems and policies.

Exploring risk in early adolescent African American youth.

Two studies were conducted to explore the degree to which single- and multiple-risk profiles were evident in samples of African American early adolescents in low-income inner-city, rural, and suburban schools. Study 1 examined early adolescent risk status (i.e., single, multiple) in relation to later adjustment in a representative sample (70% European American, 30% African American). Youth who experienced a single risk in early adolescence had moderately increased levels of school dropout and criminal arrests, whereas youth with multiple risks (i.e., combination of 2 or more risks) had significantly increased levels of school dropout, criminal arrests, and teen parenthood. Study 2 examined the extent to which single- and multiple-risk profiles were evident in cross-sectional samples of African American youth from low-income inner-city and rural areas. About one fourth of both the inner-city and rural samples of African American youth were composed of youth in the single-risk category. A significantly greater proportion of boys in the inner-city sample (20%) than boys in the rural sample (13%) experienced multiple risks. Girls across the rural and inner-city samples did not differ in terms of risk. Overall, more than 60% of African American youth in these two low-income samples did not evidence risk for later adjustment problems. Implications for research and intervention are discussed.

Choosing to be violence free in middle school: the student component of the GREAT Schools and Families Universal Program.

This paper describes the theoretical basis and content of the universal student component of the Guiding Responsibility and Expectations for Adolescents for Today and Tomorrow (GREAT) Schools and Families' middle school violence prevention program for changing school climate. The GREAT Student Program builds on and extends the content of the sixth grade Responding In Peaceful and Positive Ways (RIPP-6) social-cognitive violence prevention program through an expanded conceptual framework that focuses on changing school norms and explicitly incorporates cultural and contextual goals. The program consists of twenty 40-minute lessons taught by a trained facilitator on a weekly basis during the school day.

IE1-pp65 recombinant protein from human CMV combined with a nanoparticulate carrier, SMBV, as a potential source for the development of anti-human CMV adoptive immunotherapy.

BACKGROUND: Human cytomegalovirus (HCMV) infection and reactivation following allogeneic bone marrow transplantation is a major source of complications in grafted patients including pneumonitis, graft rejection and even death. Adoptive immunotherapy consisting in transfer of CD4(+) and CD8(+) T cells directed against HCMV has proved its worth. Nevertheless, established procedures have to be improved in terms of safety and waiting period required to obtain specific T cells. METHODS: As an alternative to infectious virus used in current strategies, we purified a recombinant protein IE1-pp65 resulting from the fusion of the regulatory IE1 and matrix pp65 proteins, both known as the major targets of the overall anti-HCMV T cell response. Based on our previous data demonstrating its use for in vitro stimulation and expansion of anti-HCMV CD4(+) and CD8(+) T cells (Vaz-Santiago et al, 2001, J.Virol, 75:7840-47) from peripheral blood mononuclear cells (PBMC) of seropositive donors, we planned to improve its in vitro immunogenicity through association with a nanoparticulate carrier, SMBV. RESULTS: We demonstrated that using of SMBV/IE1-pp65 formulation allowed to potentiate in vitro activation of T cells and to expand more CD8(+) T cells than with soluble IE1-pp65, following stimulation of PBMC. DISCUSSION: These data suggest the use of SMBV/IE1-pp65 formulation as a potential source of antigen for efficient T cells expansion in the development of safe anti-HCMV immunotherapy.

Ex vivo stimulation and expansion of both CD4(+) and CD8(+) T cells from peripheral blood mononuclear cells of human cytomegalovirus-seropositive blood donors by using a soluble recombinant chimeric protein, IE1-pp65.

The transfer of anti-human cytomegalovirus (HCMV) effector T cells to allogeneic bone marrow recipients results in protection from HCMV disease associated with transplantation, suggesting the direct control of CMV replication by T cells. IE1 and pp65 proteins, both targets of CD4(+) and CD8(+) T cells, are considered the best candidates for immunotherapy and vaccine design against HCMV. In this report, we describe the purification of a 165-kDa chimeric protein, IE1-pp65, and its use for in vitro stimulation and expansion of anti-HCMV CD4(+) and CD8(+) T cells from peripheral blood mononuclear cells (PBMC) of HCMV-seropositive donors. We demonstrate that an important proportion of anti-HCMV CD4(+) T cells was directed against IE1-pp65 in HCMV-seropositive donors and that the protein induced activation of HLA-DR3-restricted anti-IE1 CD4(+) T-cell clones, as assessed by gamma interferon (IFN-gamma) secretion and cytotoxicity. Moreover, soluble IE1-pp65 stimulated and expanded anti-pp65 CD8(+) T cells from PBMC of HLA-A2, HLA-B35, and HLA-B7 HCMV-seropositive blood donors, as demonstrated by cytotoxicity, intracellular IFN-gamma labeling, and quantitation of peptide-specific CD8(+) cells using an HLA-A2-peptide tetramer and staining of intracellular IFN-gamma. These results suggest that soluble IE1-pp65 may provide an alternative to infectious viruses used in current adoptive strategies of immunotherapy.

Escape of human cytomegalovirus from HLA-DR-restricted CD4(+) T-cell response is mediated by repression of gamma interferon-induced class II transactivator expression.

Human cytomegalovirus (HCMV), a betaherpesvirus, is a pathogen which escapes immune recognition through various mechanisms. In this paper, we show that HCMV down regulates gamma interferon (IFN-gamma)-induced HLA-DR expression in U373 MG astrocytoma cells due to a defect downstream of STAT1 phosphorylation and nuclear translocation. Repression of class II transactivator (CIITA) mRNA expression is detected within the first hours of IFN-gamma-HCMV coincubation and results in the absence of HLA-DR synthesis. This defect leads to the absence of presentation of the major immediate-early protein IE1 to specific CD4(+) T-cell clones when U373 MG cells, used as antigen-presenting cells, are treated with IFN-gamma plus HCMV. However, presentation of endogenously synthesized IE1 can be restored when U373 MG cells are transfected with CIITA prior to infection with HCMV. Altogether, the data indicate that the defect induced by HCMV resides in the activation of the IFN-gamma-responsive promoter of CIITA. This is the first demonstration of a viral inhibition of CIITA expression.

Unusual expression pattern of the MHC class I Q5k gene in the AKR mouse: possible role in embryo development.

Analysis of the tissue-specific expression of the Q5k gene in the AKR mouse reveals an unusual expression pattern. The Q5k mRNA is present in embryos from day 12, but expression is switched off in most tissues except thymus and testis shortly after birth. Late in pregnancy the gene is again transcribed in females. Analysis at the epitope level, with a Qa-2 specific monoclonal antibody revealed that in most cases the Q5k product is confined to the cytoplasm. These results suggest that Q5k has a most unusual tissue distribution and timing of expression among all the H-2 class I and Q genes so far described.

Biochemical analysis of a novel H-2 class I-like glycoprotein expressed in five AKR-(Gross virus) derived spontaneous T cell leukemias.

The H-2 class I Ag profiles of five spontaneous AKR (H-2K) Gross virus leukemic cell lines were analyzed. A novel H-2 class I, "alloantigen"-like glycoprotein was immunoprecipitated and isolated from all the tumor cell lines using an H-2Dd-specific mAb 35-5-8. The novel Ag was also recognized in vitro by anti-H-2Dd-specific CTL. In addition, DNA from all the thymomas, but not the DNA from normal adult AKR thymic cells showed a transcribed gene detectable with an H-2Dd-specific oligonucleotide probe. The molecular profile of the novel antigen was further studied by two-dimensional gel electrophoresis and analyzed by a computer based image analyzer system and reverse-phase HPLC tryptic peptide mapping. Its molecular pattern was different from the syngeneic H-2Kk, H-2Dk, and the allogeneic H-2Dd gene products. The two-dimensional gel pattern of the novel H-2 class I molecule had a different overall structure reflected in isoelectric point, number, and distribution of polypeptide spots. The tryptic peptide map analysis showed six peaks exclusively identified with the novel Ag. The calculated degree of homology with the corresponding H-2Dd, H-Dk, and H-Kk peptides was 41, 56, and 51%, respectively. In addition, an unusual cell surface distribution of the novel Ag was observed in most of the leukemic lines. The removal of sialic acid residues by neuraminidase treatment facilitated the detection of the allodeterminants by anti-H-2Dd-specific mAb and CTL. Furthermore, we showed that in one AKR tumor line, 424, there is a close association of the novel Ag with the syngeneic class I molecules. Prior preclearance of the syngeneic class I molecules revealed the presence of the H-2Dd-like allospecificity. The genetic and molecular relationship between the expression of this novel class I-like glycoprotein and the recently sequenced Q5 gene is under current investigation.