Download No Slide Title - University of Colorado

Impact of Metabolism on
Immune Response:
Implications for Neurological
Repair
Authors
Biology Department:
M. Karen Newell
E.Villalobos-Menuey
Physics Department:
R. E. Camley, Z. Celinski and T. M. Christensen
University of Colorado at Colorado Springs,
Colorado Springs, CO
Key Idea:
Energy metabolism, the efficient use of fuels for energy,
and the consequent levels of intracellular reactive oxygen
species, directly impacts the expression of molecules
recognized by the immune system.
Consequences:
If we understand how to manipulate metabolism, we can
facilitate effective repair and regeneration of defective tissues.
How does immune
recognition work?
T-cells (white blood cells) travel through the body
checking to see if you are okay.
Several things can happen:
If your cells are okay – T-cells leave you alone.
If your cells are not okay, T-cells can either
1) destroy damaged cells
2) fix damaged cells by promoting regeneration
3) attract other cells to promote repair
Metabolism and Cancer
• Protection from Reactive Oxygen
How do T Cells Work?
The outside of T-cells have two types of receptors
that must be engaged to activate the cell.
Each receptor "looks for" a different structure on the
cell being recognized.
These structures are:
1) Peptides in association with MHC
2) B7 or Fas – providing costimulation and
thought to be the result of
damage or danger
(see picture)
Response of Breast Cancer Cells to
Microwaves
When breast cancer cells are exposed to 10 GHz
microwave radiation (2 mWatts) both metabolic and
immune recognition levels increase.
The effect persists at least 21 hours after microwave
treatment.
Response of Breast Cancer
Cells to Microwaves
Response of Breast Cancer
Cells to Microwaves
1.2
3000
30 Min.
2500
30 Min.
1 Hr.
3 Hr.
2000
1500
1000
0.8
3 Hr.
0 Min.
0.6
0.4
0 Min.
500
0.2
0
0
MCF7 Cells
MCF7 Cells
Time of Microwave Treatment
Time of Microwave Treatment
Effects of Microwaves 21 Hours
After Treatment
Effects of Microwaves 21
Hours After Treatment
1.2
3500
3 Hr.
3000
1
30 Min.
30 Min.
1 Hr.
3 Hr.
1 Hr.
2500
0.8
Level of B7
Level of Reactive Oxygen (Measure of
Change in Metabolic Activity)
1 Hr.
1
Level of B7
Level of Reactive Oxygen (Measure of
Change in Metabolic Activity)
3500
2000
1500
0 Min.
0 Min.
0.6
0.4
1000
0.2
500
0
0
MCF7 Cells
MCF7 Cells
Time of Microwave Treatment
Time of Microwave Treatment
Can we cause changes in immune
recognition?
We saw that microwaves produce changes in reactive oxygen
(measure of metabolic change) and immune recognition.
Can the addition of reactive oxygen (H2O2) by itself cause
differences in immune recognition?
The data below shows the answer is yes!
Levels of B7
Leukemic Cell Lines
48 Hours Incubation in Reactive Oxygen
4
3
No Treatment
2
.25 mM Reactive
Oxygen
1
0
U937
HL60
Can we cause changes in immune
recognition by other methods?
We saw that adding reactive oxygen (H2O2) changes immune
recognition. We can ask if other substances that also alter the
metabolism can change immune recognition. We investigate
-- yes
2) Insulin
-- yes
3) Drugs
-- yes
Levels of Fas
(CD95)
1) Glucose
Leukemic Cell Lines
Changes in Immune Recognition Signals
20
15
No Treatment
With Treatment
10
5
0
Remove Glucose
Add Insulin
Can we cause changes in immune
recognition in neurons?
YES!
Our very recent experiments show the addition of reactive oxygen
(H2O2) to neurons induces significant increases in expression of
B7.
Neuronal Cell Lines
24 Hours Incubation in Reactive Oxygen
Levels of B7
4
3
No Treatment
2
.25 mM Reactive
Oxygen
1
0
PC12
PC12TRK
Neurons and T Cells
Sometimes T cells attack the myelin sheath, as in
multiple sclerosis.
If we can prevent T cell attack, we can reduce the
severity of the disease.
T cells can also facilitate repair of neurons! If we can
promote T cell repair, we can help repair spinal cord
injuries.
(see picture)
Metabolism and Cancer
• Protection from Reactive Oxygen
Implications for Neural Systems
We have seen that changes in cellular metabolism
dramatically impact immune recognition.
Why is this important?
The answer is that if we can change how the immune
system recognizes a cell, we may be able to direct the
immune system to repair, regenerate, or destroy the
recognized cell.
This could help all of the following:
Neural repair -- helping stroke victims
Neural regeneration -- helping people with spinal
cord injuries
Destruction of tumor cells -- helping those with
brain tumors
Immune system attacks of healthy tissue -- helping
those with MS or preventing
graft rejection.
Leishmania: Lysosomal pH In
Susceptible and Resistant
Strains of Mice
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Levels of Reactive Oxygen
In Resistant versus Susceptible
Strains of Mice
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