Biomedical subjects

Matthias G Von Herrath

Publications and source records attributed to Matthias G Von Herrath.

4 recordsLinked to original sources

PubMed2004

IP-10 and type 1 diabetes: a question of time and location.

Chemokines are key signal molecules that attract cells of the host immune system to the site of a potential threat. Virus infections usually induce a massive chemokine and cytokine burst and therefore recruit a large plethora of leukocytes to the site of infection with the goal to restrict and abrogate viral spread. The down side of this massive excitation of the human defense system is non-specific activation of potentially self-reactive lymphocytes. Coupled with an antigen-specific event, for example molecular mimicry between host commponents and viral proteins, autoimmunity might be the consequence in susceptible individuals. However, activated immune components with autoaggressive potential must find their target and must remain in one site sufficiently long in order to cause chronic tissue damage. In this review we will focus on the influence of the chemokine IP-10 (CXCL10) on the trafficking of autoaggressive cells during the immunopathogenesis of type 1 diabetes (T1D) and explain why IP-10 can have a dual effect on T1D depending on time and location of expression.

Animals↗

PubMed2003

Preferential escape of subdominant CD8+ T cells during negative selection results in an altered antiviral T cell hierarchy.

Negative selection is designed to purge the immune system of high-avidity, self-reactive T cells and thereby protect the host from overt autoimmunity. In this in vivo viral infection model, we show that there is a previously unappreciated dichotomy involved in negative selection in which high-avidity CD8(+) T cells specific for a dominant epitope are eliminated, whereas T cells specific for a subdominant epitope on the same protein preferentially escape deletion. Although this resulted in significant skewing of immunodominance and a substantial depletion of the most promiscuous T cells, thymic and/or peripheral deletion of high-avidity CD8(+) T cells was not accompanied by any major change in the TCR V beta gene family usage or an absolute deletion of a single preferred complementarity-determining region 3 length polymorphism. This suggests that negative selection allows high-avidity CD8(+) T cells specific for subdominant or cryptic epitopes to persist while effectively deleting high-avidity T cells specific for dominant epitopes. By allowing the escape of subdominant T cells, this process still preserves a relatively broad peripheral TCR repertoire that can actively participate in antiviral and/or autoreactive immune responses.

Animals↗

PubMed2003

Using regulatory APCs to induce/maintain tolerance.

It is well established that antigen-presenting cells (APCs) such as dendritic cells (DCs) possess potent immune-stimulatory function. They are considered to be the key driving element for most immune, autoimmune, and host-defense responses. However, recent evidence suggests that as much as APCs can turn things on, they also have the capability to turn things off. To summarize the evidence for such regulatory function of APCs is the purpose of this review article. We are just beginning to understand whether regulatory APC function can be mapped to a separate lineage of APCs or whether it is more commonly acquired under certain maturation conditions. Furthermore, it becomes apparent that it is important to consider differences between human and mouse DCs as well as splenic-, lymph node-, or blood-derived APCs. We believe that, in the upcoming years, better understanding of positive and negative roles of APCs in immune regulation will benefit both sides of APC therapy: their use in enhancing immunity, for example, in vaccine design and cancer, as well as their application for the treatment of autoimmunity.

Animals↗

PubMed2002

Apoptosis of autoreactive CD8 lymphocytes as a potential mechanism for the abrogation of type 1 diabetes by islet-specific TNF-alpha expression at a time when the autoimmune process is already ongoing.

The role of TNF-alpha in type 1 diabetes pathogenesis is controversial. Using double transgenic mice expressing (i) the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV) as an islet self-antigen and (ii) TNF-alpha under control of a tetracycline-regulated promotor system (tTA) in the pancreatic beta cells, we could previously demonstrate a differential effect of TNF-alpha on the incidence of type 1 diabetes. Most interestingly, late expression of TNF-alpha resulted in a reversion of mice that were already diabetic to a nondiabetic state. Here we provide a model of how experienced autoaggressive CD8 lymphocytes are dying by apoptosis as a result of beta cell-specific TNF-alpha expression at a time when the autoimmune process is already ongoing.

Animals↗