Linking CD4 Gene Expression
and T Cell Development Pp.523-532
Gerald
Siu
Anti-CD45RB
Monoclonal Antibody-Mediated Transplantation Tolerance Pp.533-543
P.P.W.
Luke, C.A. O’Brien, A.M. Jevnikar and R. Zhong
How
Does HIV Cause Depletion of CD4 Lymphocytes? A Mechanism Involving Virus
Signaling Through its Cellular Receptors Pp.545-550
Miles
W. Cloyd, Jenny J.Y. Chen, Patrick Adeqboyega and Liqiang Wang
Molecular
Mechanisms of Pulmonary Fibrosis and Current Treatment Pp.551-573
Kazuyoshi
Kuwano, Naoki Hagimoto and Nobuyuki Hara
Nucleic
Acid Enzymes as a Novel Generation of Anti-gene Agents Pp.575-588
Mouldy
Sioud
Receptors
for Unopsonized Particles: The Role of Alveolar Macrophage Scavenger Receptors
Pp.589-595
Aiyappa
Palecanda and Lester Kobzik
Regulation
of Apoptosis and Cell Cycle Activity in Rheumatoid Arthritis Pp.597-608
Harris
Perlman, Lisa J. Pagliari and Michael V. Volin
Linking
Genomics to Immunotherapy by Reverse Immunology – ‘Immunomics’ in the New Millennium
Pp.609-619
B.
Maecker, M.S. von Bergwelt-Baildon, K.S. Anderson, R.H. Vonderheide and J.L.
Schultze
The
Functional and Clinical Roles of Osteopontin in Cancer and Metastasis Pp.621-632
Kara
A. Furger, Rajashree K. Menon, Alan B. Tuck, Vivien H.C. Bramwell and Ann F.
Chambers
[Back to top] Linking CD4 Gene Expression
and T Cell Development
Gerald Siu
The
control of CD4 gene expression is essential for proper T lymphocyte
development. Signals transmitted from the T-cell antigen receptor (TCR) during
the selection process are believed to be linked to the regulation of CD4 gene
expression during specific stages of T cell development. Thus, the control CD4
gene expression is an ideal model system for studying the molecular mechanisms
that drive T cell development. Here, I discuss the characterization of
transcriptional control elements in the CD4 locus and the factors that mediate
their function. The study of these elements has led to significant insights
into the mechanisms in which the T lymphocyte develops it mature functional
characteristics.
[Back to top] Anti-CD45RB Monoclonal Antibody-Mediated Transplantation
Tolerance
P.P.W. Luke, C.A. O’Brien, A.M. Jevnikar and R. Zhong
Currently, lifelong immunosuppression is required for organ
transplant recipients. The majority of transplant recipients will eventually
develop chronic rejection with resultant graft loss, despite treatment with
powerful immunosuppressive agents. These agents are also associated with
numerous toxicities including reduced immunity against infection and
malignancy. Therefore, the central goal in transplant science is to devise
tolerance strategies in an attempt to establish a state of prolonged
non-reactivity against the allograft, accompanied with preservation of an
intact immune system. Although predictable tolerance induction has been
elusive, we found that short course of the novel immunomodulatory agent,
anti-CD45RB monoclonal antibody, leads to indefinite acceptance of renal
allografts in mice, and has been shown to markedly prolong allograft survival
in primates. We review the current state of development of this antibody, and
the progress made in defining its mechanism of action.
[Back to top] How Does HIV Cause Depletion of CD4 Lymphocytes? A Mechanism
Involving Virus Signaling Through its Cellular Receptors
Miles W. Cloyd, Jenny J.Y. Chen, Patrick Adeqboyega and Liqiang Wang
HIV infection causes an acquired immunodeficiency, principally because of depletion of CD4 lymphocytes. The mechanism by which the virus depletes these cells, however, is not clearly understood. Since the virus predominantly infects CD4 lymphocytes in vivo, some have assumed that HIV replication directly kills the infected cells or that the anti-HIV immune response destroys them. However, a large number of studies do not support this concept. Rather, the data strongly indicate that CD4 lymphocyte depletion is by an indirect mechanism. Several theories on various direct and indirect mechanisms are reviewed. The most plausible mechanism, which is backed by in vivo data, involves the consequences of HIV contact with resting CD4 lymphocytes, which cannot support virus replication. HIV binding to, and signaling through, CD4 and chemokine receptor molecules on resting CD4 lymphocytes and other cell types [which extensively occurs as the rare, productively infected cells (ie: infected cells producing virus) migrate among other cells through the lymphoid tissues back into the blood] induces upregulation of L-selectin and Fas. When these resting, HIV-signaled CD4 cells return to the blood, they home very rapidly back to peripheral lymph nodes and axial bone marrow, and their disappearance from the blood is likely due to their leaving the circulatory system. Approximately one-half of these cells that have been induced by HIV to home to lymph nodes are subsequently induced into apoptosis during the process of trans-endothelial migration when secondary signals are received through various homing receptors. These cells are not making HIV, which would explain the observation that CD4 cells not making HIV are the predominant cells dying in the lymph nodes of HIV+ subjects. These studies indicate that the principal mechanism of CD4 T-cell depletion by HIV is due to its use of CD4 as its primary receptor and the signaling induced through this receptor on nonpermissive (resting) T-lymphocytes. This unique mechanism of viral pathogenesis, if correct, leads to the possibility that HIV might not cause depletion of CD4 lymphocytes if it used some other receptor to infect CD4 lymphocytes
[Back to top] Molecular Mechanisms of Pulmonary Fibrosis and Current
Treatment
Kazuyoshi Kuwano, Naoki Hagimoto and Nobuyuki Hara
Pulmonary
fibrosis is a common response to various insults or injuries to the lung.
Although there are various initiating factors or causes, the terminal stages
are characterized by proliferation and progressive accumulation of connective
tissue replacing normal functional parenchyma. The pathogenesis of pulmonary
fibrosis includes endothelial and epithelial cell injury, production of
inflammatory cells and their mediators, and fibroblast activation. Conventional
therapy consisting of glucocorticoids or cytotoxic drugs is usually ineffective
in preventing progression of the disease. Further understanding of the
molecular mechanisms of endothelial and epithelial cell injury, inflammatory
reaction, fibroblast proliferation, collagen deposition and lung repair, should
lead to the development of effective treatments against pulmonary fibrosis.
Accordingly, this review summarizes recent progress made in understanding the
molecular mechanisms of pulmonary fibrosis. A detailed discussion is presented
regarding each of the potential new therapies which have emerged from the
animal models of pulmonary fibrosis and which have been developed through
advances in cellular and molecular biology.
[Back to top] Nucleic Acid Enzymes as a Novel Generation of
Anti-gene Agents
Mouldy
Sioud
Recent molecular and cellular studies have highlighted the important role of some gene products in the cause and/or perpetuation of human pathological conditions including cancer and autoimmune diseases. The identification of such gene products has led to the development of new candidate therapies. The discovery of catalytic nucleic acid enzymes has provided researchers with a potentially important tool to block the expression of abnormal genes, provided that their sequences are known. The cleavage specificity of these compounds is determined by their hybridizing antisense arms, which anneal with the target mRNA in a complementary fashion. Nucleic acid enzymes can be delivered to cells either endogenously as gene encoding RNA enzymes (ribozymes) or exogenously as in vitro made agents. Given the progress reported during the last years, a wide range of molecular designs and chemical modifications can be introduced into these compounds, in particular the hammerhead type ribozyme. Here, we review the design, stability and the therapeutic application of these agents with the goals of illustrating relevant gene targets and signal pathways for molecular medicine. Relevant in vivo problems of the technology, mRNA repair by group I intron ribozymes and gene regulation by endogenous RNA will also be discussed.
[Back to top] Receptors for Unopsonized Particles: The Role of Alveolar
Macrophage Scavenger Receptors
The lung is constantly exposed to potentially pathogenic particles and microorganisms. Alveolar macrophage (AM) binding of inhaled environmental particles is a critical first step in phagocytosis and clearance, and must be accomplished without the benefit of opsonization by specific antibodies. Opsonin-independent phagocytosis is initiated by direct recognition of phagocytic target. The identities of receptors on AMs that mediate unopsonized particle binding were, until recently, not known. Using flow cytometry, monoclonal antibody and expression cloning techniques we have found a major role for the scavenger receptor, MARCO in AM binding of particles and bacteria. In this review we will discuss the role of scavenger receptors in AM binding of unopsonized particles and the use of flow cytomety in analyzing AM-particle interaction. We will also discuss other non-scavenger receptors involved in opsonin-independent phagocytosis.
[Back to top] Regulation of Apoptosis and Cell Cycle Activity in Rheumatoid
Arthritis
Harris Perlman, Lisa J. Pagliari and Michael V. Volin
The regulation of proliferation and cell death is vital for homeostasis, but the mechanisms that coordinately balances these two events in rheumatoid arthritis (RA) remains largely unknown. In RA, the synovial lining increases through enhanced proliferation, migration, and/or decreased cell death. The aberrant decrease in apoptosis or increased cell cycle activity of fibroblast-like or macrophage-like synoviocytes is responsible for the synovial hyperplasia and contributes to the destruction of cartilage and bone. Recently, numerous molecules that modulate apoptosis and cell cycle have been implicated to play a role in RA. This review will describe the current understanding of the molecular mechanisms that govern apoptosis and cell cycle and their relationship to RA pathogenesis.
[Back to top] Linking Genomics to Immunotherapy by Reverse Immunology –
‘Immunomics’ in the New Millennium
B. Maecker, M.S. von
Bergwelt-Baildon, K.S. Anderson, R.H. Vonderheide and J.L. Schultze
The disclosure of the human genome sequence and rapid advances in genomic expression profiling have revolutionized our knowledge about molecular changes in malignant diseases. Rapidly growing gene expression databases and improvements in bioinformatics tools set the stage for new approaches using large-scale molecular information to develop specific therapeutics in cancer. On one hand, the ability to detect clusters of genes differentially expressed in normal and malignant tissue may lead to widely applicable targeting of defined molecular structures. On the other hand, analyzing the ‘molecular fingerprint’ of an individual tumor raises the possibility of developing customized therapeutics. One approach to use the emerging new datasets for the development of novel therapeutics is to identify genes that are specifically expressed in tumors as targets for immune intervention. This review will focus on the process from in silico analysis of expression databases and screening of potential candidate genes by bioinformatics to the in vitro and in vivo analysis to determine the immunogenicity of candidate tumor antigens. Basic biological principles of 'reverse immunology' as well as technical advantages and difficulties will be addressed.
[Back to top] The Functional and Clinical Roles of Osteopontin in Cancer
and Metastasis
Kara A. Furger, Rajashree K. Menon, Alan B. Tuck, Vivien H.C. Bramwell and Ann F. Chambers
Osteopontin (OPN) is a secreted and integrin-binding protein that has been implicated in a number of pathologies. In this review we will focus on the functional and clinical roles of OPN in cancer and metastasis, with a particular emphasis on breast cancer. While much evidence has suggested that OPN is associated with cancer, its functional contribution to cancer remains poorly understood. Here we will review evidence for mechanisms by which OPN may act to enhance malignancy, including evidence that signaling pathways directly induced by OPN, as well as interactions with growth factor receptor pathways, can combine to activate expression of genes and functions that contribute to metastasis. OPN has been shown to be over-expressed in a variety of human tumors and is present in elevated levels in the blood of some patients with metastatic cancers. We also will discuss recent clinical evidence that suggests that OPN is not only associated with several tumor types, but that levels of OPN in cancer patients’ blood or tumors may provide prognostic information.