Page 104 - Binder2

Because in the long run, the difference between rejection
and tolerance isn’t the antigen.
It’s the narrative the immune system hears—and
dendritic cells are writing the first draft.

But most biologics are delivered in ways that bypass this
system completely.
They don’t enter through the nose, gut, or lungs—where
the immune system has evolved to sample and assess the
outside world with nuance. They aren’t introduced gently,
repeatedly, or in a way that suggests safety. Instead, they
arrive abruptly—injected into muscle, skin, or directly
into the bloodstream—routes the immune system has
been trained over millennia to associate with injury,
infection, or danger.

These delivery routes trigger heightened surveillance.
Antigen-presenting cells in the blood stream are activated.
+
These aren’t the CD103 dendritic cells of our gut, these are
+
macrophages, B cells, and CD11b dendritic cells. And
once the immune system detects a foreign protein in that
context, it does exactly what it’s supposed to do: mount a
defense.

To make matters worse, most biologics are given in large,
infrequent doses. From an immune perspective, that’s the
equivalent of a molecular ambush. There is no gradual
exposure. No opportunity for regulatory T cells to assess
and suppress the response. No signals that say, this belongs
here. The immune system is offered no reason to trust the
drug—only reasons to suspect it.

And eventually, it does more than suspect.
It rejects.

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