In vivo measurement of lymphocyte kinetics during immune reconstitution after hematopoietic stem cell transplantation using [6,6-2H2]-glucose labeling

Hematopoietic stem cell transplantation (HSCT) often provides the best chance
for a cure for many malignant and non-malignant diseases. Conditioning regimens
are however intense and render the immune system and in particular the T
lymphocyte compartment depleted for extended periods of time. This puts HSCT
patients at an increased risk to develop opportunistic infections and about
10-20% of stem cell transplant recipients even die of infectious complications.
Enhancing immune reconstitution following stem cell transplantation is
therefore an area of intensive research.
Much of our understanding of immune reconstitution and in particular lymphocyte
recovery following stem cell transplantation is based on irradiated mouse
models and in humans on longitudinal descriptive studies of reappearing
lymphocyte subsets in the blood. We will study lymphocyte recovery dynamics in
patients who underwent HSCT by measuring lymphocyte production rates and life
spans through in vivo stable-isotope labeling with [6,6-2H2]-glucose
(deuterated glucose). A better understanding of lymphocyte recovery dynamics
will offer new venues to develop approaches to enhance immune recovery
following HSCT.

To get more insight into lymphocyte kinetics during immune reconstitution after
hematopoietic stem cell transplantation

All participants will be admitted to the AMC for a 24-hour infusion of
[6,6-2H2]-glucose. Label decay will be followed for a period up to 6 months.
The amount of label within sorted lymphocyte subsets of interest will be
measured at predetermined intervals using gas chromatography mass spectrometry
(GC/MS). With the help of mathematical models the production rates and life
spans of these lymphocyte subsets can then be calculated.

- Benefit: Using in vivo deuterated glucose labeling we will study turnover
rates of lymphocyte subsets (such as naïve, memory, effector CD4 and CD8 T
cells, B cells and NK cells) following HSCT, to obtain a better understanding
of adaptive immune recovery following HSCT. This is much needed to develop new
approaches to shorten the time that HSCT patients are at increased risk to
develop opportunistic infections (group benefit). There is no personal benefit
for the participants.

- Burden: During [6,6-2H2]-glucose labeling (up-labeling phase): 24-hour
admission to the AMC for continuous i.v. [6,6-2H2]-glucose administration;
blood draw before labeling (one venapuncture; 56 ml); blood sampling through
finger pricks every 4 hours starting after one hour of labeling. After labeling
(down-labeling phase): blood sampling through venapunctures (56 ml per draw) at
predetermined intervals after infusion up until 6 months after labeling. Total
volume of blood drawn (including t=0): 9 x 56 ml of blood = 504 ml in 6 months.
- Risks: Deuterium is a naturally occurring, stable isotope that has been
applied a.o. to study glucose and adipocyte metabolism and lymphocyte turnover
in healthy adults, elderly individuals and HIV-infected patients. It has an
excellent safety profile. Apart from occasional mild transient vertigo or
dizziness during label infusion no side effects have been reported.