Biology Reference
In-Depth Information
Table 14.3
Approaches to Improving Transplant Outcomes
Prevention of GVHD without affecting GVT/GVL
SelectiveT-celldepletionofstemcellgraft
CD3T-celldepletion
CD8T-celldepletion
Ex vivo
or
in vivo
depletionofactivatedTcells
T-cellselection
MemoryT-cellselection
Tregselection
Delayeddonorlymphocyteinfusion
Manipulationofcytokines
Anti-TNF-
α
andIL-1antibodies
IL-11
Anti-BAFFtherapies
The principal and first line treatment of cGVHD remains corticosteroids.
However, corticosteroids are associated with a suboptimal response rate,
with up to 20% of patients requiring additional therapies; among respond-
ers only slightly more than half of patients are successfully weaned from
corticosteroids
[118]
. The addition of cyclosporin and/or thalidomide
to the upfront therapy of cGVHD has not resulted in significant benefit
[118,119]
. The optimal therapy for steroid-refractory cGVHD is not well
defined but includes immunomodulatory approaches such as mycophe-
nolate mofetil (MMF), sirolimus, extracorporeal photophoresis (ECP),
alemtuzumab, and tyrosine kinase inhibitors such as imatinib and others.
Based on work discussed elsewhere in this chapter, the administration of
IL-2 to enhance Treg number and function, and drugs that target B cells,
such as rituximab, have also shown promise in the treatment of steroid-
refractory cGVHD
[9,69-77]
.
313
IMMUNOMODULATORY APPROACHES
MMF is an antimetabolite that functions by inhibiting the only pathway
of purine synthesis functional in lymphocytes; it is associated with a
69-77% response rate in steroid-refractory cGVHD
[120-122]
. Sirolimus,
an inhibitor of mammalian target of rapamycin, has been used in com-
bination with the calcineurin inhibitors such as cyclosporin or Tacroli-
mus with good response rates but with additional toxicity related to the
drug's narrow therapeutic window
[123-125]
. ECP is thought to work by
several mechanisms, including inducing apoptosis in all white blood cell
lines, decreasing the production of proinflammatory and increasing the
production of anti-inflammatory cytokines, decreasing the stimulation of
effector T cells and increasing the number of Tregs, and, more recently,
potentially by decreased BAFF levels and the survival of alloreactive B cells
[126,127]
. It results in responses in up to 63% of patients in some studies
[128,129]
. There has been more limited experience using the anti-CD52
monoclonal antibody alemtuzumab for the treatment of steroid-refrac-
tory cGVHD but, as was discussed previously, it has been used both in
transplant conditioning and in graft preparation for T-cell depletion with
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