Strategies to improve posttransplant immunity - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 124

to the thymus; and in addition to IFN-γ, both TRAIL and Fas ligand were
found to be critical for donor T-cell attack of thymic stroma [45] . Given the
multiple factors involved in impairment of thymopoiesis during GVHD,
it should also be noted that thymic GVHD occurs within the context of a
larger lymphohematopoietic GVHD that can also damage the bone mar-
row microenvironment, leading to a loss of extrathymic lymphoid lineage
precursors that must seed the thymus for T-cell development to occur [46] .
Finally, the clinical implications of thymic GVHD may be even broader than
the impairment in immune reconstitution and resultant susceptibilities to
infection and malignant relapse [3,47] , as impaired negative selection of
host-reactive T-cell precursors undergoing intrathymic T-cell development
during thymic GVHD has been proposed as the pathophysiological mecha-
nism for the development of chronic GVHD [48-50] . In summary, GVHD
results in damage to thymic architecture and function as well as major
impairments in immune reconstitution following clinical hematopoietic
transplantation, and experimental modeling has identified both patho-
physiological mechanisms of thymic GVHD as well as potential targets for
clinical intervention.
126
Interleukin-7
Interleukin-7 (IL-7) is a 25-kDa glycoprotein produced by stromal tissues in
the thymus and bone marrow [51] , epithelial cells such as keratinocytes [52]
and intestinal epithelium [53] , follicular dendritic cells and other dendritic
cells [54] . The IL-7 receptor consists of a specific α chain (CD127) and the
common γ chain, and is expressed on lymphocyte precursors, thymocytes,
and on most mature T cells, as well as on immature B cells [54] . IL-7 has
a broad range of biological activities (reviewed in reference [54] ). IL-7 is a
non-redundant growth factor for lymphopoiesis, notably for thymopoiesis
as demonstrated by B- and T-cell deficiencies in IL-7 − / − or IL-7 R − / − knock-
out mice [55, 56] . Patients with mutations in IL-7Rα suffer from severe com-
bined immunodeficiency (SCID) with severe T-cell depletion and absence
of cellular or humoral immunity, confirming that IL-7 is essential for T-cell
development in man [57] . In patients with T-cell deficiency due to various
causes (HIV infection, chemotherapy for cancer, allogeneic HSCT) there
is an inverse relationship between circulating IL-7 levels and peripheral
CD4 + T-cell counts [58-60] . In contrast, no relationship has been observed
between circulating lymphocyte count and IL-2, IL-4, IL-6, IL-12 or IL-15,
suggesting that IL-7 is a key regulator of T-cell homeostasis [60] .
IL-7 has several effects on developing thymocytes. It enhances the viabil-
ity of thymocytes in vitro through the modulation of anti-apoptotic Bcl-2
family members [54,61] . In concert with other growth factors such as SCF,
IL-7 induces the proliferation of T-cell precursors, notably during the early
CD4 − CD8 − (“double negative”) stage of development [62] . Furthermore
IL-7 appears to be involved in T-cell receptor rearrangement [63] . Finally
IL-7 plays an essential role in the generation and maintenance of thymus-
derived γδ T cells [64,65] .
IL-7 also affects mature T cells and acts as a lymphoid trophic factor, inhib-
iting apoptosis in mature T lymphocytes through the upregulation of Bcl-2