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

36 The DuCa Model
Figure 5.8 A plot based on the findings
of Stoffels et al. (2004) that apoptotic as
well as necrotic β-cells implies cytokine
secretion. The implications of this
in terms of the model of Marée et al.
(2006) is that the Balb/c-mouse becomes
diabetic as well.
cytotoxic cytokines that the Balb/c macrophages do not have or that the NOD-βcells
become necrotic faster than the Balb/c-β-cells; i.e. d is higher in NOD-mice.
We have, however, not been able to find any publications that report this. A totally
other possibility is that the cytokines secreted upon ingestion of an apoptotic β-cell
is not cytotoxic. As we learned in section 2.2 not all cytokines are cytotoxic, some
stimulate differentiation and stimulation, in agreement with the observation of Sreenan
et al. (1999) of increased β-cell proliferation before onset of T1D in NOD-mice (Sreenan
et al., 1999, p.992), i.e. during the preceding inflammation.
All things aside it is interesting that Marée et al. (2006) partially base their hypothesis
on the Stoffels et al. (2004) article, without mentioning that according to Stoffels et al.
(2004) phagocytosis of apoptotic cells also leads to release of cytokines.
Activation by phagocytosis of necrotic β-cells
A curious thing is that the resting macrophages do not become activated via phagocytosis
of necrotic β-cells. If we assume that the activation rate due to phagocytosis of
necrotic cells is equal to that due to apoptotic cells we could include activation due to
phagocytosis of necrotic cells by introducing a −f1MBn-term in equation 5.6, and a
+f1MBn-term in equation 5.7. In figure 5.9 we have done simulations with these additional
terms, for NOD and Balb/c parameters. To the right we have Balb/c behavior,
on the left we have the NOD behavior. When we compare figure 5.9 to 5.3, we see that
assuming that resting macrophages become activated through phagocytosis of necrotic
cells imposes some noticeable differences during the initial face, but apart from that
there is no difference.
If we look at the graphs for the Balb/c parameters, the most obvious difference is that
the cytokines hardly make an appearance (when we use a logarithmic concentration).
At the same time, the apoptotic and necrotic cells have a significantly smaller max
concentration. This is naturally because initially there is a higher concentration of
active macrophages compared to simulations of the DuCa model without activation
from necrotic cells. With activation due to necrotic cells, the concentration of active
macrophages grows rapidly until it reaches a logarithmic concentration of approxi-