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In-Depth Information
resultant decreased rates of GVHD at the expense of increased infection
and disease relapse. For the treatment of cGVHD, it was recently tested
in combination with rituximab with a resultant response rate of 100% at
30 days of treatment; at 90 days, however, only 50% of patients had ongo-
ing responses and 21% of patients had relapsed cGVHD
[130]
. In addi-
tion, alemtuzumab results in severe immunosuppression with associated
infection-related morbidity and mortality.
Although not an immune-suppressive agent, imatinib has recently been
evaluated for the treatment of cGVHD. This grew out of an observation
that imatinib treatment for relapsed CML following ASCT in a patient with
concurrent bronchiolitis obliterans resulted in improvement in pulmonary
function
[131]
. Since then small cohorts of patients with cGVHD have been
treated with this tyrosine kinase inhibitor, resulting in response rates rang-
ing from 50% to 80% depending on the site of disease
[132,133]
. Imatinib is
thought to work through its effects on the fibrotic activity of platelet-derived
growth factor receptor and TGF-β pathways.
Treg EXPANSION
314
The importance of Treg function in the achievement of immune tolerance
following ASCT has resulted in the investigation of ways to expand Treg
numbers and function in the transplant recipient.
Ex vivo
Treg expansion
or selection is one avenue that has been explored but until now has been
difficult to achieve
[134,135]
. The administration of IL-2 to patients receiv-
ing DLI resulted in greater numbers of Tregs following therapy than did IL-2
administration or DLI alone, and this was not associated with GVHD
[61]
.
In vivo
expansion with IL-2 for the treatment of cGVHD has recently been
studied. Low-dose IL-2 was found to be safe when administered to patients
with steroid-refractory cGVHD following ASCT and resulted in disease
response in 52% of patients, with stable disease in an additional 48%, and
a preferential expansion of functional Tregs
[9]
. On average these patients
were approximately 3 years post-transplantation, were on steroids, and had
failed a median of two prior therapies for cGVHD. Over half of the patients
received IL-2 for an extended period of time past the intended 12-week
study period, with a median duration of treatment of 13 months (range
2-36 months). There was one complete response at 14 months and three
additional patients improved such that they could completely discontinue
steroids between 12 and 36 months. Overall steroid doses were decreased
by a mean of 60%. Treg counts were significantly lower than in healthy con-
trols at the initiation of therapy but rose rapidly, peaking at over eight times
median baseline level by 4 weeks. They then declined but remained signifi-
cantly elevated above baseline for at least 4 weeks off treatment. There was
no significant change in Tcons during or after treatment so the Treg/Tcon
ratio was significantly increased over baseline during and following treat-
ment. There were also no significant effects on numbers of CD8 T cells,
CD3
+
CD56
+
NKT cells, or CD19 B cells, but there was a significant increase
in NK cells during treatment; NK cell numbers fell during the 4-week follow-
up off treatment so that they were not significantly different from baseline.
This study demonstrates the dynamic kinetics of immune reconstitution
following transplantation and the ability to manipulate those kinetics to
achieve a new homeostasis with an improvement in clinical outcomes.
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