Oral Presentations - Federation of Clinical Immunology Societies

S14 Abstracts
of molecules that are likely to be critical to the
maturation and function of DCs. In contrast, downstream
NF-kappaB activity, DC maturation, and NEMO polyubiquitination
were normal in EDI DCs following stimulation with
the TLR4 ligand. These results show for the first time that
CD40 and TLR4 use different signaling pathways to
ubiquitinate NEMO, and offer insight into how a mutation
in the zinc finger domain of NEMO leads to pathway
specific defects in NF-kappaB signaling and thus immune
deficiency.
doi:10.1016/j.clim.2007.03.208
OR.28 Treatment of HIV-infected Patients with
Vitamin D-binding Protein Derived Macrophage
Activating Factor (GcMAF) Eradicates HIV-Infection
Nobuto Yamamoto, Director, Socrates Institute for
Therapeutic Immunology, Philadelphia, PA, Masumi Ueda,
Immunology, Chief, Microbiology, Philadelphia, PA,
Charles Benson, Head, Infectious Diseases, School of
Veterinary Medicine, University of Pennsylvania, Kennett
Square, PA
Serum vitamin D-binding protein (known as Gc protein) is
the precursor for the principal macrophage activating factor
(MAF). The MAF precursor activity of serum Gc protein of
HIV-infected patients was lost or reduced because Gc
protein is deglycosylated by serum α-N-acetylgalactosaminidase
(Nagalase) secreted from HIV-infected cells. Since
Nagalase is the intrinsic component of gp120, serum
Nagalase activity is the sum of enzyme activities expressed
in both HIV virions and envelope proteins released from HIVinfected
cells. Because of Nagalase being an HIV viral
protein and immunogenic, serum Nagalase was already
complexed with anti-HIV immunoglobulin G (IgG) in patient
blood stream. These antibodies, however, were largely not
neutralizing antibodies. The IgG-bound viral proteins
retained Nagalase activity that deglycosylates Gc protein.
Therefore, macrophages of HIV-infected patients having
deglycosylated Gc protein cannot be activated, leading to
immunosuppression. Stepwise treatment of purified Gc
protein with immobilized beta-galactosidase and sialidase
generated the most potent macrophage activating factor
(termed GcMAF), which produces no side effect in humans.
Macrophages activated by administration of GcMAF
(100 ng/patient) develop a large amount of Fc receptors
as well as enormous variation of receptors that recognize
IgG bound and unbound HIV virions. Thus, macrophages
activated by GcMAF preferentially phagocytize IgG-bound
HIV virions via Fc receptor mediation. Cells latently
infected with HIV are unstable and spontaneously release
the virions at a high rate. After less than 18 weekly
administrations of 100 ng GcMAF for twenty-one nonanemic
patients, they exhibited low serum Nagalase activities
equivalent to healthy controls, indicating eradication of HIV
infection.
doi:10.1016/j.clim.2007.03.209
OR.29 Impaired In Vitro Regulatory T Cell Function
Associated with Wiskott-Aldrich Syndrome
Marsilio Adriani, Visiting Fellow, NIH/NHGRI, Bethesda, MD,
Joseph Aoki, Visiting Fellow, NIH/NHGRI, Bethesda, MD,
Reiko Horai, Postdoctoral Fellow, NIH/NHGRI, Bethesda,
MD, Akihiro Kon, England Postdoctoral, Fellow, Bethesda,
MD, Angela M. Thornton, Staff Scientist, NIH/NIAID,
Bethesda, MD, Martha Kirby, Senior Research Assistant,
NIH/NHGRI, Bethesda, MD, Stacie M. Anderson, Senior
Research Assistant, NIH/NHGRI, Bethesda, MD, Richard M.
Siegel, Investigator, NIH/NIAMS, Bethesda, MD, Pamela L.
Schwartzberg, Investigator, NIH/NHGRI, Bethesda, MD,
Fabio Candotti, Senior Investigator, NIH/NHGRI, Bethesda,
MD
Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency
characterized by thrombocytopenia, eczema, recurrent
infections and high incidence of malignancy. This disease is
caused by mutations of the WAS protein (WASP) gene, a key
regulator of actin polymerization. WAS patients show high
incidence of autoimmune disorders (∼40–70%) the occurrence
of which, however, does not correlate with the severity of the
other classical hallmarks of the disease. A central question in
understanding the pathophysiology of WAS is why immunodeficient
patients develop symptoms suggestive of hyperactivation
of immune compartments, such as eczema and autoimmune
diseases. Since defects in CD4+CD25+ regulatory T cells (Treg)
have been associated with autoimmunity, we examined the
presence and function of these cells in WAS patients and Waspdeficient
mice. Wasp-deficient patients and mice develop Treg
cells that express Foxp3 with no detectable differences in
frequency compared to controls. However, in vitro suppression
assays showed that these Treg cells have impaired inhibitory
function in vitro,which,inmice,couldonlybepartiallyrescued
by pre-activation with exogenous IL-2. The demonstration of
impaired in vitro suppressor function in WASp-deficient Treg
cells suggests that defective regulatory Tcell function may be an
important factor contributing to immune dysregulation in WAS.
doi:10.1016/j.clim.2007.03.210
OR.30 Regulatory T Cell Abnormalities Associated
with Aberrant CD4+ T Cell Responses in Patients
with Immune Reconstitution Disease (IRD)
Nabila Seddiki, Research Fellow, Centre For Immunology
and National Centre in HIV Epidemiology and Clinical
Research (UNSW), Darlinghurst
Up to 30% of patients with HIV commencing antiretroviral
therapy (ART) late in the disease restore a pathogen-specific
cellular immune response that is immunopathological and
causes disease referred as immune reconstitution disease or
IRD. The immunopathogenesis of IRD is not well understood and
is likely to be a consequence of an aberrant reconstitution of
certain T cell subsets. In a cross-sectional study, using HIV
patients who developed mycobacterial IRD, we show that in
comparison to those starting ARTand not developing IRD, CD4+ T
cells specific for MTB and M. avium complex (MAC) antigens,
produce high levels of IFN-g and IL-2 (Pb0.01) and proliferate
strongly when compared to controls. We postulated that deficits
in regulatory T cells (Tregs) numbers may play a central role in