Biomedical subjects

J L Van Hemmen

Publications and source records attributed to J L Van Hemmen.

4 recordsLinked to original sources

PubMed2001

Th1 or Th2: how an appropriate T helper response can be made.

Two types of T helper (Th) cells have been defined on the basis of their cytokine secretion patterns. The decision of a naive T cell to differentiate into Th1 or Th2 is crucial, since to a first approximation it determines whether a cell-mediated or humoral immune response is triggered against a particular pathogen, which profoundly influences disease outcome. Here we show that the internal behaviour of the T helper system, which emerges from regulatory mechanisms 'built into' the T helper system, itself can usually select the appropriate T helper response. This phenomenon arises from an initial Th1 bias together with the induction of Th1-->Th2 switches when Th1 effectors do not lead to efficient antigen clearance. The occurrence of these shifts is based on the antigen dose dependence of T helper differentiation, which is a consequence of asymmetries in cross-suppression. Critical for this feature is the rate with which Th2 cells undergo antigen-induced cell death.

Animals↗

PubMed2000

Cytokine-modulated regulation of helper T cell populations.

Helper T (Th) cells are a crucial component of the adaptive immune system and are of fundamental importance in orchestrating the appropriate response to pathogenic challenge. They fall into two broad categories defined by the cytokines each produces. Th1 cells produce interferon- gamma and are required for effective immunity to intracellular bacteria, viruses and protozoa whereas Th2 produce IL-4 and are required for optimal antibody production to T-dependent antigens. A great deal of experimental data on the regulation of Th1 and Th2 differentiation have been obtained but many essential features of this complex system are still not understood. Here we present a mathematical model of Th1/Th2 differentiation and cross regulation. We model Fas-mediated activation-induced cell death (AICD) as this process has been identified as an important mechanism for limiting clonal expansion and resolving T cell responses. We conclude that Th2 susceptibility to AICD is important for stabilizing the two polarized arms of the T helper response, and that cell-cell killing, not suicide, is the dominant mechanism for Fas-mediated death of Th1 effectors. We find that the combination of the anti-proliferative effect of the cytokine TGF- beta and the inhibiting influence of IL-10 on T cell activation are crucial controls for Th2 populations. We see that the strengths of the activation signals for each T helper cell subset, which are dependent on the antigen dose, co-stimulatory signals and the cytokine environment, critically determine the dominant helper subset. Switches from Th1- to Th2-dominance may be important in chronic infection and we show that this phenomenon can arise from differential AICD susceptibility of T helper subsets, and asymmetries in the nature of the cross-suppressive cytokine interactions. Our model suggests that in some senses a predominantly type 2 reaction may well be the "default" pathway for an antigen-specific immune response, due to these asymmetries.

Apoptosis↗

PubMed1996

Vertical signal flow and oscillations in a three-layer model of the cortex.

A model of vertical signal flow across a layered cortical structure is presented and analyzed. Neurons communicate through spikes, which evoke an excitatory or inhibitory postsynaptic potential (spike response model). The layers incorporate two anatomical features-dendritic and axonal arborization patterns and distance-dependent time delays. The vertical signal flow through the network is discussed for various stimulus conditions using two different, but typical, axonal arborization patterns. We find stationary as well as oscillatory response, but the oscillatory response may be restricted to a single layer. Confronted with conflicting stimuli the network separates the patterns through phase-shifted oscillations. We also discuss two hypothetical animals, to be called "cat" and "mouse." These have different axonal arborizations, which give rise to a different oscillatory response (if any) of the various layers.

Axons↗

PubMed1994

Central immune system, the self and autoimmunity.

We model how auto-reactive B cells are kept under control by an idiotypic network. Autoimmunity occurs when the control is broken by an infection or not achieved through an abnormal ontogenetic evolution. We describe the idiotypic network, viz., the central immune system, by idiotype-anti-idiotype pairs which are coupled to a set of highly connected clones, which interact with each clone of the network. Some clones of the central immune system recognize self-antigen. We find a huge variety of fixed points which can be classified as tolerant, autoimmune, and neutral states according to the concentration of the auto-reactive antibody. Most significant are auto-reactive clones which are a member of an idiotype-anti-idiotype pair. In a healthy individual, an autoimmune disease is induced by an antigen infection which triggers a transition from a tolerant to an autoimmune state. Autoimmunity is induced more readily by an antigen coupling to the anti-idiotype than by one interacting with the auto-reactive clone itself. We indicate a possible therapy which simply reverses the processes that have lead to the autoimmune disease. In the early development of the central immune system its highly connected, core part serves to draw the more specific clones of idiotype-anti-idiotype pairs into the network. In order to avoid autoimmunity in ontogenetic evolution the anti-idiotype of an auto-reactive clone must be formed in advance by a sufficiently long period of time. Thus, a well ordered succession of the appearance of the more specific clones is required.

Animals↗