Current
The Enigma of Dendritic Cell-Immunodeficiency
Virus Interplay Pp.229-248
I.
Frank and M. Pope
Manipulation of CD45 Antigen in
Transplantation Tolerance Pp.249-255
Saiho
Ko, Mark D. Jaeger, Marc H. Dahlke, Yoshiyuki Nakajima and Hans J. Schlitt
Regulation of T cell Apoptosis during the
Immune Response Pp.257-272
Sven
Baumann, Andreas Krueger, Sabine Kirchhoff and Peter H. Krammer
Cyclic ADP-ribose (cADPR) and Nicotinic Acid
Adenine Dinucleotide Phosphate (NAADP): Novel Regulators of Ca2+-Signaling and Cell Function Pp.273-282
Andreas
H. Guse
Current Developments in Human Molecular
Cytogenetic Techniques Pp.283-297
Thomas
Liehr and Uwe Claussen
A New Insight into the Pathogenesis of
Filarial Disease Pp.299-302
Mark
J. Taylor
Function of Cytokines within the TGF-b
Superfamily as Determined from Transgenic and Gene Knockout Studies in Mice Pp.303-327
Ashok
B. Kulkarni, Tamizchelvi Thyagarajan and John J. Letterio
[Back to top] The Enigma of Dendritic Cell-Immunodeficiency
Virus Interplay
I. Frank and M. Pope
A dendritic cell
(DC) encountering an immunodeficiency virus should pose a threat to the virus,
by efficiently processing and presenting viral antigenic determinants to
activate specific anti-viral T and B cell immunity. While this may occur in
vivo, it is apparent that DC-entrapped viruses can freely spread between cells,
move to distal tissues, and proliferate rapidly particularly upon meeting CD4+ T
cells. In fact, the latter is further augmented when the T cells are activated.
Thus, it seems that immunodeficiency viruses exploit the unique ability of DCs
to survey the periphery and capture incoming pathogens, traffic around the body
often targeting the lymphoid tissues, and efficiently communicate with na•ve
and memory T cells. Combined with the fact that DCs are likely the first
leukocytes interacting with virions crossing the mucosae, these features
provide the basis on which the virus maximizes its chance to establish
infection even in the face of immune activation. How this is actually achieved
by the virus is still an enigma. Herein, we intend to summarize what is known
about how distinct DC subsets and immunodeficiency viruses interact, what
cellular and viral factors influence these events, and how this drives virus
replication versus stimulation of protective immunity. Clarifying these issues
is necessary to define the exact role of DCs in the transmission and dissemination
of HIV infection, to facilitate the development of methods to improve the
immune-activating capacity of DCs as well as the design of strategies to
prevent DC-driven infection.
[Back to top] Manipulation of CD45 Antigen in
Transplantation Tolerance
Saiho Ko, Mark D. Jaeger, Marc H. Dahlke, Yoshiyuki
Nakajima and Hans J. Schlitt
CD45 is known to
have tyrosine phosphatase activity for signal transduction of T cells. Immunomodulation
of CD45 has been tried to prevent T cell-mediated graft rejection in organ
transplantation. In vitro study showed that blockade of CD45RB, an alternative
splicing isoform of CD45, inhibited proliferative response of T cells after
allogeneic stimulation. Treatment with a monoclonal antibody (mAb) against
CD45RB induced long-term allograft acceptance in some mouse organ
transplantation models. In a rat heart allograft model, a single injection of
anti-rat CD45 (RT7) mAb which bound to allomorphic region of RT7 also induced
allograft acceptance.
CD45/RT7 is also a
useful tool of targeting hematopoietic cells, because of the selective
expression on all hematopoietic cells. There are two allomorphic forms of CD45
(RT7a and RT7b) in the rat. Using RT7 system, a rat heart
allograft model from RT7a donors to RT7b recipients was
designed to test functional relevance of graft-associated hematopoietic cells
(microchimerism) to allograft acceptance. Then donor-derived hematopoietic
cells were selectively depleted using anti-RT7a mAb in vivo.
Depletion on day 0 prevented allograft acceptance and was associated with
severe acute or chronic graft rejection, while depletion on day 18 after
transplantation showed no effect. This experimental study showed a crucial role
of microchimerism in induction phase of allograft acceptance.
In conclusion, the
CD45/RT7 system is not only a target molecule for tolerance induction, but also
an useful tool for experimental models in transplantation immunology. In this
review, we introduce basic properties of CD45 and recent results with
manipulation of CD45.
[Back to top] Regulation of T cell Apoptosis during the
Immune Response
Sven Baumann, Andreas Krueger, Sabine Kirchhoff and
Peter H. Krammer
Apoptosis of
T-lymphocytes is a fundamental process regulating antigen receptor repertoire
selection during T cell maturation and homeostasis of the immune system. It
also plays a key role in elimination of autoreactive lymphocytes. Resting
mature T cells are activated by antigen to elicit an appropriate immune
response. In contrast, preactivated T cells undergo activation-induced cell
death (AICD) in response to TCR triggering alone. Thus, death by apoptosis is
essential for function, growth and differentiation of T-lymphocytes. This
review focuses on apoptosis mechanisms involved in T cell development and
during the course of an immune response.
[Back to top] Cyclic ADP-ribose (cADPR) and Nicotinic Acid
Adenine Dinucleotide Phosphate (NAADP): Novel Regulators of Ca2+-Signaling and Cell Function
Andreas H. Guse
Ca2+
ions are involved in the regulation of many diverse functions in animal and
plant cells, e.g. muscle contraction, secretion of neurotransmitters, hormones
and enzymes, fertilization of oocytes, and lymphocyte activation and
proliferation. The intracellular Ca2+ concentration can be increased by different
molecular mechanisms, such as Ca2+ influx from the extracellular space or Ca2+
release from intracellular Ca2+ stores. Release from intracellular Ca2+
stores is accomplished by the small molecular compounds D-myo-inositol
1,4,5-trisphosphate (InsP3), cyclic ADP-ribose (cADPR) and nicotinic acid
adenine dinucleotide phosphate (NAADP). This review concentrates on (i)
receptor-mediated formation of cADPR by ADP-ribosyl cyclases, (ii)
intracellular and extracellular effects of cADPR in a variety of cell types,
and (iii) cADPR in the nucleus. Though our understanding of the role of NAADP
is still unclear in many aspects, important recent findings are reviewed, e.g.
Ca2+ release activity and binding studies in
mammalian cell types.
[Back to top] Current Developments in Human Molecular
Cytogenetic Techniques
Thomas Liehr and Uwe Claussen
In the last decade
a variety of fluorescence in situ hybridization (FISH) assays have been
developed. In this paper we present an overview on the currently available
methods in molecular cytogenetics, highlighting their advantages and
limitations, as well as their applications. Even though one has to be impressed
by the total number of new techniques introduced in molecular cytogenetics, one
has to be aware of the fact that it is not the brilliance of a technique that
is important but the scientific question that can be addressed by it. In this
review special emphasis has given in describing possible strategies for the
characterization of marker and derivative chromosomes in tumor- and clinical
cytogenetics.
[Back to top] A New Insight into the Pathogenesis of
Filarial Disease
Mark J. Taylor
Filariasis is a
major public health problem throughout many regions of the tropics. The disease
is caused by several species of filarial nematode including Wuchereria
bancrofti and Brugia malayi, the agents of lymphatic filariasis, and Onchocerca
volvulus, the cause of ‘riverblindness’. Disease caused by these worms varies
depending on the tissue location of the parasite, and is associated with
episodes of acute and chronic inflammation. These pathologies, including
elephantiasis and blindness, rank among the most disabling in the world.
Studies aimed at characterizing the molecular nature of the inflammatory
stimuli derived from filarial nematodes uncovered a long forgotten secret,
their symbiont Wolbachia. LPS-like molecules from these intracellular bacteria
are responsible for potent inflammatory responses from macrophages and in
animal models of filarial disease. Wolbachia has also been associated with severe
inflammatory reactions to filarial chemotherapy, being released into the blood
following the death of the parasite. Recent studies in animal models even
implicate Wolbachia in the onset of lymphodema and blindness. Taken together
these studies suggest a major role for Wolbachia in the pathogenesis of
filarial disease. It may be possible, through the use of antibiotic therapy, to
clear worms of their bacteria, in the hope that this will prevent the onset and
development of filarial pathology.
[Back to top] Function of Cytokines within the TGF-b
Superfamily as Determined from Transgenic and Gene Knockout Studies in Mice
Ashok B. Kulkarni, Tamizchelvi Thyagarajan and John J.
Letterio
Several major conceptual problems regarding specific in vivo functions of the TGF-ß family members remain the key focus of many researchers studying the biology of these secreted signaling molecules. More than 45 members of this family of growth factors have been identified and partially characterized for their molecular roles in numerous processes such as cell proliferation and differentiation, embryonic development, carcinogenesis, immune dysfunction, inflammation and wound healing. The high degree of similarity that exists at the structural level among the isoforms of these growth factors is accompanied by a significant overlap in function, as defined by many in vitro model systems and in vivo systems involving administration of exogenous ligand or of ligand-specific blocking antibodies. The ability to discern the critical functions of these molecules based on patterns of expression has also often been quite difficult. The evolution of more sophisticated functional genomics approaches has been recently instrumental in generating unique perspectives into the mechanisms governing the activity of the members of the TGF -b family. The studies outlined in this review are significant in that they not only support working hypotheses regarding the activities of TGF-b generated through extensive in vitro studies but also raise new questions regarding the role of each isoform in numerous processes. With the rapid advances in these approaches to probe activity in a more cell and time-dependent fashion, we will gain valuable insights for designing approaches for targeting the complex cellular pathways mediating their responses and will also help us develop novel therapies to treat disease processes.