nr. 477 - 2011 - Institut for Natur, Systemer og Modeller (NSM)

20 The DuCa Model
macrophages prevents the ignition of the feedback loop in these mice.
The following list summarizes the events that lead up to the sustained apoptosis of
β-cells in NOD-mice.
1. An apoptotic wave occurs.
2. The resting macrophages become activated when they engulf an apoptotic β-cell.
3. The activated macrophages, being as (in)efficient as the inactivated macrophages
are unable to clear all the apoptotic β-cells.
4. As some of the β-cells are left uncleared too long they enter necrosis.
5. The activated macrophages engulf necrotic β-cells as well as apoptotic β-cells. The
phagocytosis of necrotic cells causes the active macrophages to secrete cytokines.
6. Some of the cytokines are cytotoxic to β-cells, thus causing more β-cells to undergo
apoptosis.
7. As more β-cells undergo apoptosis the NOD macrophages will be more and more
overburdened thus more β-cells will become necrotic, which amplifies the detrimental
feedback mechanism.
This should not be understood as though these things happen in a consecutive order,
rather they take place more or less concurrently. For example the instance the apoptotic
wave starts macrophages begin to become activated, a concentration of necrotic cells
arise and so also a concentration of cytokines etc.
To give a proper critique of the DuCa model we most now what the purpose of it is.
This leads us to our next section.
5.2 Purpose of Marée et al. (2006)
The purpose of Marée et al. (2006) is to answer the following questions (Marée et al.,
2006, p.1269)
• Can the difference in macrophage phagocytosis function in NOD versus
Balb/c mice (alone, or in combination with other factors) account
for the distinct fates of these two strains, i.e. possible initiation of
autoimmunity in NOD but not in Balb/c mice?
• Can the wave of β-cell death associated with normal development in all
mice be a triggering stimulus that initiates the inflammation in NOD
mice?
using a mathematical model that retains the most important features of the preface of
T1D, i.e. continued β-cell destruction, based on a less is more concept (Marée et al.,
2006, p.1269).
They do not want to construct a mathematical model that incorporates every detail
involved in the onset of T1D, in agreement with our thoughts on mathematical modelling;
cf. chapter 4.
One example of their parsimonious approach is their handling of cytokines (and other
harmful factors). In chapter 2 we learned that several cytokines play a role in the etiology
of T1D (Blasio et al. (1999)), but Marée et al. (2006) lump all of these together
in one compartment (Marée et al., 2006, p.1276).
Marée et al. (2006) emphasizes that this mathematical model is based on the NOD