Measles
Virus Induced Immunosuppression: Targets
and Effector Mechanisms Pp. 163-181
Sibylle
Schneider-Schaulies, Stefan Niewiesk, Jürgen Schneider-Schaulies and Volker ter
Meulen
The Molecular Pathogenesis and Experimental Therapy of IgA Nephropathy: Recent Advances and Future DirectionsPp. 183-196
Stephen I-Hong Hsu
Molecular
Mechanisms of Thiamine Utilization Pp. 197-207
Charles K. Singleton and
Peter R. Martin
Macrophage
Response to Mycobacterium tuberculosis During HIV Infection: Relationships
Between Macrophage Activation and Apoptosis Pp.
209-216
Mariani F, Goletti D.,
Ciaramella A., Martino A., Colizzi V. and Fraziano M.
DNA
Vaccines Pp. 217-243
Arturo Reyes-Sandoval
and Hildegund C.J. Ertl
Adeno-Associated
Virus (AAV) as a Vehicle for Therapeutic Gene Delivery: Improvements in Vector
Design and Viral Production Enhance Potential to Prolong Graft Survival in
Pancreatic Islet Cell Transplantation for the Reversal of Type 1 Diabetes Pp.
245-258
M.H. Kapturczak, T.
Flotte and M.A. Atkinson
Molecular Analysis of Primary Central Nervous System and Primary Intraocular Lymphomas Pp. 259-272
N. Tuaillon and C.C.
Chan
Diabetes Mellitus-Cell Transplantation and Gene Therapy
Approaches Pp. 273-286
Tanya Halvorsen and Fred
Levine
[Back
to top] Measles Virus Induced
Immunosuppression: Targets and
Effector Mechanisms
Sibylle Schneider-Schaulies,
Stefan Niewiesk, Jürgen Schneider-Schaulies and Volker ter Meulen
A profound, transient suppression of immune functions during and after the acute infection is the major cause of more than one million cases of infant deaths associated with measles worldwide. Concommittant with the generation of an efficient measles virus (MV) specific immunity, immune responses towards other pathogens are strongly impaired and provide the basis for the establishment and severe course of opportunistic infections. The molecular basis for MV-induced immunosuppression has not been resolved as yet. Similar to other immunosuppressive viruses, MV is lymphotropic and viral nucleic acid and proteins are detectable in peripheral blood mononuclear cells (PBMC). It is considered central to MV-induced immunosuppression that PBMC isolated from patients largely fail to proliferate in response to antigen specific and polyclonal stimulation. The low abundancy of MV-infected PBMC suggests that MV-induced immunosuppression is not directly caused by infection-mediated cell loss or fusion, but rather by indirect mechanisms such as deregulation of cytokines or surface contact-mediated signaling which may lead to apoptosis or impair the proliferative response of uninfected PBMC. Evidence for a role of any of these mechanisms was obtained in vitro, however, much has still to be learned about the tropism of MV and its interactions with particular host cells such as dendritic cells in vivo.
[Back to top] The Molecular Pathogenesis and Experimental Therapy of IgA
Nephropathy: Recent Advances and Future Directions
Stephen
I-Hong Hsu
In 1968 Berger and Hinglais published the first description of IgA nephropathy (IgAN). In the ensuing 30 years, extensive clinical, epidemiologic, and immunologic characterizations of primary (idiopathic) glomerulonephritis with IgA as the predominant or co-dominant immunoglobulin deposited in the mesangia of all glomeruli, have established the features of IgAN as a distinct glomerular disease entity. Despite these efforts, the basic molecular mechanism(s) which mediate abnormal mesangial IgA deposition with ensuing extracellular matrix expansion and mesangial cell proliferation remains poorly understood, definitive diagnosis still depends on histologic examination of renal biopsy specimens, and widely accepted standards for effective therapy remain to be defined.
This review will begin with a
summary of the earlier “descriptive” histopathologic and clinical epidemiologic
work which firmly established the distinct immunohistologic features of IgAN,
the most common glomerulonephritis among patients undergoing renal biopsy and a
major cause of renal failure worldwide. In recent years, a series of important
advances in the areas of molecular pathogenesis and experimental therapy have
emerged, reflected in a "molecular" paradigm shift in the techniques
and approaches applied to the study of IgAN. Representative studies will be
critically evaluated to highlight both the strengths and potential weaknesses
of each of these approaches. Throughout, the author will offer a personal
perspective on promising areas of new investigation and potential approaches to
the identification of disease/susceptibility genes involved in the development
and progression of IgAN, the application of these discoveries through the
development of clinically useful molecular diagnostic tests, and the rational
design of novel therapeutic strategies.
[Back
to top] Molecular Mechanisms of
Thiamine Utilization
Charles
K. Singleton and Peter R. Martin
Thiamine is required for all tissues and is found in high concentrations in skeletal muscle, heart, liver, kidneys and brain. A state of severe depletion is seen in patients on a strict thiamine-deficient diet in 18 days, but the most common cause of thiamine deficiency in affluent countries is alcoholism. Thiamine diphosphate is the active form of thiamine, and it serves as a cofactor for several enzymes involved primarily in carbohydrate catabolism. The enzymes are important in the biosynthesis of a number of cell constituents, including neurotransmitters, and for the production of reducing equivalents used in oxidant stress defenses and in biosyntheses and for synthesis of pentoses used as nucleic acid precursors. Because of the latter fact, thiamine utilization is increased in tumor cells. Thiamine uptake by the small intestines and by cells within various organs is mediated by a saturable, high affinity transport system. Alcohol affects thiamine uptake and other aspects of thiamine utilization, and these effects may contribute to the prevalence of thiamine deficiency in alcoholics. The major manifestations of thiamine deficiency in humans involve the cardiovascular (wet beriberi) and nervous (dry beriberi, or neuropathy and/or Wernicke-Korsakoff syndrome) systems. A number of inborn errors of metabolism have been described in which clinical improvements can be documented following administration of pharmacological doses of thiamine, such as thiamine-responsive megaloblastic anemia. Substantial efforts are being made to understand the genetic and biochemical determinants of inter-individual differences in susceptibility to development of thiamine deficiency-related disorders and of the differential vulnerabilities of tissues and cell types to thiamine deficiency.
[Back to top] Macrophage Response to Mycobacterium tuberculosis During HIV
Infection: Relationships Between Macrophage Activation and Apoptosis
Mariani
F, Goletti D., Ciaramella A., Martino A., Colizzi V. and Fraziano M.
Human macrophages represent the first line of defense for the containment of Mycobacterium tuberculosis infection. After phagocytosis, macrophages express activation surface markers and produce proinflammatory cytokines and chemokines whose main role is to control pathogen spreading by recruiting peripheral lymphocytes and monocytes at the site of inflammation. However, in the case of a concomitant human immunodeficiency virus (HIV) infection, these signals strongly enhance the susceptibility to viral infection both at the viral entry and replication levels. Under these conditions, viral expansion extends beyond tissue macrophages to T cells and vice-versa, according to the emerging viral phenotype. In absence of an efficient immune response, Mycobacterium tuberculosis can replicate in macrophages in an uncontrolled fashion culminating in macrophage death by apoptosis. As a consequence, a more severe form of immunedepression, involving both innate and specific immune responses, could be responsible for both ematogenous mycobacterial dissemination and extrapulmonary form of tuberculosis in HIV-infected patients.
[Back to top] DNA Vaccines
Arturo Reyes-Sandoval and Hildegund C.J. Ertl
Within the last decade bacterial plasmids encoding foreign antigens have revolutionized vaccine design. Although no DNA vaccine has yet been approved for routine human or veterinary use, the potential of this vaccine modality has been demonstrated in experimental animal models. Plasmid DNA vaccination has shown efficacy against viral, bacterial and parasitic infections, modulated the effects of autoimmune and allergic diseases and induced control over cancer progression. With a better understanding of the basic immune mechanisms that govern induction of protective or curative immune responses, plasmid DNA vaccines and their mode of delivery are continuously being optimized. Because of the simplicity and versatility of these vaccines, various routes and modes of delivery are possible to engage the desired immune responses. These may be T or B effector cell responses able to eliminate infectious agents or transformed cells. DNA vaccines may also induce an immunoregulatory/modulatory or immunosuppressive (tolerizing) response that interferes with the differentiation, expansion or effector functions of B and T cells. In this sense a DNA vaccine may be thought of as a ‘negative’ vaccine. Pre-clinical and initial small-scale clinical trials have shown DNA vaccines in either of these modes to be safe and well tolerated. Although DNA vaccines induce significant immune responses in small animal trials their efficacy in humans has so far been less promising thus necessitating additional optimizations of this novel vaccine approach.
[Back to top] Adeno-Associated Virus (AAV) as a Vehicle for Therapeutic
Gene Delivery: Improvements in Vector Design and Viral Production Enhance
Potential to Prolong Graft Survival in Pancreatic Islet Cell Transplantation
for the Reversal of Type 1 Diabetes
M.H. Kapturczak, T. Flotte and M.A. Atkinson
Most viral gene delivery systems
utilized to date have demonstrated significant limitations in practicality and
safety due to the level and duration of recombinant transgene expression as
well as their induction of host immunogenicity to vector proteins. Recombinant
adeno-associated virus (rAAV) vectors appear to offer a vehicle for safe,
long-term therapeutic gene transfer; factors afforded through the propensity of
rAAV to establish long-term latency without deleterious effects on the host
cell and the relative non-immunogenicity of the virus or viral expressed transgenes.
The principal historical limitation of this vector system, efficiency of rAAV-mediated
transduction, has recently
observed a dramatic increase as the titer, purity, and production capacity of
rAAV preparations have improved. In terms of systems that could benefit from
such improvements, rAAV gene therapy to enhance solid organ transplantation
would appear an obvious choice with islet transplantation forming a promising
candidate due to the ability to perform viral transductions ex vivo. Currently,
islet transplantation can be used to treat type 1 diabetes yet persisting
alloimmune and autoimmune responses represent major obstacles to the clinical
success for this procedure. The delivery of transgenes capable of interfering
with antigenic recognition and/or cell death [e.g., Fas ligand (FasL), Bcl-2,
Bcl-XL] as well as imparting tolerance/immunoregulation [e.g.,
interleukin(IL)-4, IL-10, transforming growth factor (TGF)-b], or cytoprotection [e.g., heme oxygenase-1
(HO-1), catalase, manganese superoxide dismutase (MnSOD)] may prevent recurrent
type 1 diabetes in islet transplantation and offer a promising form of
immunotherapy. Research investigations utilizing such systems may also provide
information vital to understanding the immunoregulatory mechanisms critical to
the development of both alloimmune and autoimmune islet cell rejection
mechanisms and recurrent type 1 diabetes.
[Back to top] Molecular Analysis of Primary Central Nervous System and Primary
Intraocular Lymphomas
N.
Tuaillon and C.C. Chan
Primary central nervous system
lymphoma (PCNSL) is usually a large B-cell, high grade non-Hodgkin's lymphoma
(NHL) classified as a diffuse large cell lymphoma (DLCL). In rare cases,
however, T cell lymphomas have been described. Although a relatively rare tumor,
the incidence of PCNSL has increased dramatically over the past 15 years in
both immuno-competent and immuno-compromised patients. The disease is
aggressive with a 5-year survival rate of less than 25 %. The cause of death is
progressive and recurrent disease in the CNS, despite aggressive
treatment. Approximately 20-25% of patients with PCNSL also have primary
intra-ocular lymphoma (PIOL). PCNSL and PIOL are closely related and
inter-connected pathologies involving two immune privileged sites.
The study of PCNSL and PIOL has been limited due to
the fact that viable malignant cells are rare and difficult to recognize.
Moreover, the cells are difficult to culture and to date there is no good
animal model for the disease. Here, we will present the current literature on
the disease. In particular, we will present data suggesting that PCNSL in
immuno-compromised and AIDS patients may correspond to two different
pathologies. Furthermore, we will discuss how the study of these lymphomas can
benefit from new advanced molecular biology techniques including single cell
PCR and laser capture microdissection (LCM). PCNSL and PIOL are aggressive
tumors, therefore, early diagnosis and prompt, aggressive treatment may improve
prognosis. Advanced molecular biology will help delineate the oncogenesis of
PCNSL and PIOL..
[Back to top] Diabetes Mellitus-Cell Transplantation and Gene Therapy Approaches
Tanya Halvorsen and Fred Levine
Diabetes mellitus affects millions of people in the United States and worldwide. It has become clear over the past decade that the chronic complications of diabetes result from lack of proper blood glucose concentration regulation, and particularly the toxic effects of chronic hyperglycemia on organs and tissues. Pancreas transplants can cure insulin-dependent diabetes mellitus (IDDM). Furthermore, recent advances in pancreatic islet isolation and immunosuppressive regimens have resulted in dramatic improvements in the survival and function of islet allografts. Therefore, islet replacement strategies are becoming increasingly attractive options for patients at risk for severe diabetic complications. A major limitation of these approaches is the small number of organs available for transplantation or islet isolation. Thus, an important next step in developing curative treatments for type I diabetes will be the generation of a replenishable source of glucose-responsive, insulin-secreting cells that can be used for beta cell replacement. This review focuses on approaches to developing robust and widely applicable beta-cell replacement strategies with an emphasis on manipulating b-cell growth and differentiation by genetic engineering.