Primary Immune Deficiency Treatment Consortium (PIDTC) report.

The Primary Immune Deficiency Treatment Consortium (PIDTC) is a network of 33 centers in North America that study the treatment of rare and severe primary immunodeficiency diseases. Current protocols address the natural history of patients treated for severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome, and chronic granulomatous disease through retrospective, prospective, and cross-sectional studies. The PIDTC additionally seeks to encourage training of junior investigators, establish partnerships with European and other International colleagues, work with patient advocacy groups to promote community awareness, and conduct pilot demonstration projects. Future goals include the conduct of prospective treatment studies to determine optimal therapies for primary immunodeficiency diseases. To date, the PIDTC has funded 2 pilot projects: newborn screening for SCID in Navajo Native Americans and B-cell reconstitution in patients with SCID after hematopoietic stem cell transplantation. Ten junior investigators have received grant awards. The PIDTC Annual Scientific Workshop has brought together consortium members, outside speakers, patient advocacy groups, and young investigators and trainees to report progress of the protocols and discuss common interests and goals, including new scientific developments and future directions of clinical research. Here we report the progress of the PIDTC to date, highlights of the first 2 PIDTC workshops, and consideration of future consortium objectives.

Preclinical development of the green tea catechin, epigallocatechin gallate, as an HIV-1 therapy.

BACKGROUND: Previously, we presented evidence that at physiologic concentrations the green tea catechin, epigallocatechin gallate (EGCG), inhibited attachment of HIV-1 glycoprotein 120 to the CD4 molecule on T cells, but the downstream effects of EGCG on HIV-1 infectivity were not determined. OBJECTIVE: To evaluate the inhibition of HIV-1 infectivity by EGCG and begin preclinical development of EGCG as a possible therapy. METHODS: PBMCs, CD4(+) T cells, and macrophages were isolated from blood of HIV-1-uninfected donors. HIV-1 infectivity was assessed by an HIV-1 p24 ELISA. Cell survival was assessed by cell viability by Trypan blue exclusion assay, cell growth by thymidine incorporation, and apoptosis by flow-cytometric analysis of annexin-V binding. RESULTS: Epigallocatechin gallate inhibited HIV-1 infectivity on human CD4(+) T cells and macrophages in a dose-dependent manner. At a physiologic concentration of 6 mumol/L, EGCG significantly inhibited HIV-1 p24 antigen production across a broad spectrum of both HIV-1 clinical isolates and laboratory-adapted subtypes (B [P < .001], C, D, and G [P < .01]). The specificity of the EGCG-induced inhibition was substantiated by the failure of EGCG derivatives lacking galloyl and/or pyrogallol side groups to alter HIV-1 p24 levels. EGCG-induced inhibition of HV-1 infectivity was not a result of cytotoxicity, cell growth inhibition, or apoptosis. CONCLUSION: We conclude that by preventing the attachment of HIV-1-glycoprotein 120 to the CD4 molecule, EGCG inhibits HIV-1 infectivity. Because this inhibition can be achieved at physiologic concentrations, the natural anti-HIV agent EGCG is a candidate as an alternative therapy in HIV-1 therapy.

Advances in basic and clinical immunology in 2006.

This article reviews the progress in the field of basic and clinical immunology in 2006, focusing on the articles published in the Journal. The role of Toll-like receptors in the immune response was explored in detail in several articles. The knowledge gained in these investigations is being used to develop strategies that enhance the immunogenicity of vaccines to prevent infectious diseases and to have an immunomodulatory effect on allergic diseases. Other components of the innate immunity reported on were the recognition of allergens with lipid-derived motifs by CD1d-restricted T cells and the role of dendritic cells in the development of an allergic response. More than 120 primary immunodeficiencies were defined at a molecular level, and biological agents such as TNF-alpha antagonists and IFN-alpha were shown to have therapeutic use. New anti-HIV drugs that block cell entry were proven to be effective, thus offering alternative therapies to respond to the development of multidrug-resistant HIV strains. The modern understanding of immunologic concepts is helping to elucidate the mechanisms of defense against viruses, bacteria, and parasites; as a result, strategies to improve management and prevention continue to emerge.

Epigallocatechin gallate, the main polyphenol in green tea, binds to the T-cell receptor, CD4: Potential for HIV-1 therapy.

BACKGROUND: The green tea flavonoid, epigallocatechin gallate (EGCG), has been proposed to have an anti-HIV-1 effect by preventing the binding of HIV-1 glycoprotein (gp) 120 to the CD4 molecule on T cells. OBJECTIVE: To demonstrate that EGCG binds to the CD4 molecule at the gp120 attachment site and inhibits gp120 binding at physiologically relevant levels, thus establishing EGCG as a potential therapeutic treatment for HIV-1 infection. METHODS: Nuclear magnetic resonance spectroscopy was used to examine the binding of EGCG and control, (-)-catechin, to CD4-IgG2 (PRO 542). Gp120 binding to human CD4+ T cells was analyzed by flow cytometry. RESULTS: Addition of CD4 to EGCG produced a linear decrease in nuclear magnetic resonance signal intensity from EGCG but not from the control, (-)-catechin. In saturation transfer difference experiments, addition of 5.8 micromol/L CD4 to 310 micromol/L EGCG produced strong saturation at the aromatic rings of EGCG, but identical concentrations of (-)-catechin produced much smaller effects, implying EGCG/CD4 binding strong enough to reduce gp120/CD4 binding substantially. Molecular modeling studies suggested a binding site for EGCG in the D1 domain of CD4, the pocket that binds gp120. Physiologically relevant concentrations of EGCG (0.2 micromol/L) inhibited binding of gp120 to isolated human CD4+ T cells. CONCLUSION: We have demonstrated clear evidence of high-affinity binding of EGCG to the CD4 molecule with a Kd of approximately 10 nmol/L and inhibition of gp120 binding to human CD4+ T cells. CLINICAL IMPLICATIONS: Epigallocatechin gallate has potential use as adjunctive therapy in HIV-1 infection.

Advances in basic and clinical immunology.

This review comments on basic and clinical immunology articles that were published in 2005, with a focus on those that appeared in the Journal of Allergy and Clinical Immunology. In the area of basic immunology, mechanisms of the innate immune system and its interaction with the adaptive immune system were described, with special consideration to applications in biodefense strategies. T regulatory cells were further characterized in their role for the control of allergic, autoimmune, and neoplastic disorders. The function of the thymus Hassall's corpuscles was reported to be the generation of T regulatory cells. Flavonoid molecules obtained from medicinal herbs, including astilbin and epigallocatechin gallate, were discovered to have immunomodulatory properties. Advances in clinical immunology resulted from efforts to develop a newborn screening test for severe combined immunodeficiency and the elucidation of the crystal structure of the IL-2 receptor gamma chain. Mutations in the membrane receptor transmembrane activator and calcium modulator and cyclophilin ligand interactor were found in patients with common variable immunodeficiency. New therapeutic options are described, such as the use of infliximab for granulomas and GM-CSF for chronic ulcers in patients with common variable immunodeficiency. The importance of mucosal immunity in acute HIV infection is cited, as is the role of CD8+ T-cell activation in HIV disease progression in children.