Biology Reference
In-Depth Information
product transfusions, pregnancies or immunization in experimental mod-
els, is attributed to cytotoxic T cells, which can be identified in alloantigen-
sensitized recipients. However, antibodies capable of recognizing MHC or
MiHA on donor cells can induce graft rejection or lineage-specific aplasia.
Immune deficiency
A major problem limiting the efficacy of allogeneic HSCT is the issue of
promoting immune reconstitution without increasing GVHD (reviewed in
chapter 6 and in reference [6]). Patients are profoundly immunosuppressed
following transplant as a result of the cytoreductive conditioning, immuno-
suppressive drugs to prevent GVHD, and the paucity of transplanted T cells
compared with the size of the T-cell compartment in an immune compe-
tent person. In addition, acute GVHD induces lymphoid hypoplasia, thus
tying GVHD to immune impairment. This leaves the patient susceptible to
a number of opportunistic infections. Infectious complications associated
with neutropenia early post-transplant are no longer as prominent in clini-
cal practice. However, cytomegalovirus, Epstein-Barr virus (EBV) and fun-
gal infections, predominantly
Candida
species and
Aspergillus fumigatus
that arise after neutrophil recovery, are now major contributors to morbid-
ity and mortality following allogeneic HSCT. Unfortunately, there are few
preclinical models that have been developed to study these opportunistic
infections and the complicating effects of GVHD on their occurrence.
4
There are two sources for T cells in the recovering recipient: peripheral
expansion of mature T cells and
de novo
production of naïve T cells derived
from transplanted stem cells and produced in the recipient thymus. How-
ever, the thymus begins to involute at puberty, and the capacity for thymic-
derived T-cell production is greatly diminished in adulthood. In addition,
the cytoreductive conditioning can induce tissue damage to the epithelial
cells of the thymus and a decreased ability to produce IL-7. Thus, a reduced
ability to generate new T cells is a function both of increasing age and of
conditioning dose intensity. An older HSCT recipient is especially prone to
limited recovery of the CD4
+
T-cell repertoire following allogeneic HSCT. A
slow recovery is associated with an increased risk of opportunistic infec-
tions and a decreased ability to generate a response to vaccination. The
benefit of
de novo
generation of T cells post-transplant is the production
of donor-derived T cells that are tolerant of both the graft and the recipient
and generation of a broad T-cell receptor (TCR) repertoire.
Enhancing immune reconstitution is an area of intensive research. An
increasing variety of approaches has been explored pre-clinically and clini-
cally: infusion of IL-7, keratinocyte growth factor, growth hormone, mature
cytotoxic lymphocytes with defined immunological properties against
pathogens or tumor antigens and blockade of sex hormones. New devel-
opments of allogeneic HSCT, e.g. umbilical cord blood or haploidentical
graft preparations leading to prolonged immunodeficiency, have further
increased the need to improve immune reconstitution. While slow T-cell
reconstitution is regarded as primarily responsible for susceptibility to
infections with viruses and fungi, GVHD and propensity for post-HSCT
relapse, the importance of innate immune cells for disease and infection
control is currently being re-evaluated. In the future, individualized therapy
Search WWH ::
Custom Search