Biology Reference
In-Depth Information
effect after allogeneic HSCT is now well accepted, the mechanisms involved
in the effect are not completely known. However, because GVHD is intimately
associated with GVL, it can be assumed that similar mechanisms control
GVHD and GVL. GVHD requires the recognition by donor T cells of anti-
gens presented by the MHC molecules on the recipient cells initiating clonal
expansion of responders and an effector response involving lymphocytes and
cytokines. In GVHD, this leads to the clinical features of acute and chronic
GVHD. In GVL reactions, the allogeneic response suppresses residual leuke-
mia. GVHD reactions are directed against a broad spectrum of tissues, includ-
ing BM. The dominant antigens on leukemia cells driving the GVL response
are not known: major or minor histocompatibility antigens co-expressed on
GVHD targets (such as normal skin and gut cells) and leukemic cells could
induce a non-specific GVH/GVL allogeneic response. The response against
either normal or malignant bone marrow-derived cells may also overlap.
Thus GVL may in part be a graft-versus-hematopoietic effect involving lym-
phoid or myeloid lineages or both. Additionally, leukemia cells could induce a
more specific allogeneic response if they express antigens, either not present
or underexpressed in cells of other tissues (reviewed in chapter 7).
Separating GVHD from GVL has been successfully accomplished in mouse
models using various strategies, including depletion of alloreactive T cells;
inhibition of inflammatory cytokines; interfering with T-cell cytolytic path-
ways, co-stimulatory pathways and trafficking; purifying T cells of certain
activation states; and using immunosuppressive cell populations, includ-
ing regulatory T cells and NK T cells
[102-104]
. NK cells have been found to
substantially contribute to GVL responses, which were previously thought
to be largely mediated by T cells alone. T-cell therapies continue to be a
major area of interest. Researchers have identified several types of antigens
that are recognized by allogeneic T cells, including various MiHAs (reviewed
in chapter 3), as well as tumor-specific antigens (reviewed in chapter 7),
including proteinase 3 (Pr3; also known as myeloblastin), Wilms' tumor 1
(WT1) and BCR-ABL. This has allowed the expansion of antigen-specific T
cells using culture techniques, in which T cells are grown
ex vivo
in the pres-
ence of APCs, the target antigen and supportive cytokines. Alternatively,
genetic engineering techniques can endow T cells with tumor-specificity
by introducing previously cloned antigen-specific T-cell receptor genes,
or modified T-cell receptor-like genes called chimeric-antigen receptors,
which recognize extracellular proteins that are expressed by tumors.
12
References
[1] Feinstein L, Sandmaier B, Maloney D, McSweeney PA, Maris M, Flowers C, et al.
Nonmyeloablative hematopoietic cell transplantation. Replacing high-dose cytotoxic
therapy by the graft-versus-tumor effect. Ann N Y Acad Sci 2001;938:328-37; discussion
337-9.
[2] Ferrara JL, Levine JE, Reddy P, Holler E. Graft-versus-host disease. Lancet
2009;373(9674):1550-61.
[3] Schleuning M. Adoptive allogeneic immunotherapy - history and future perspectives.
Transfus Sci 2000;23(2):133-50.
[4] Shlomchik WD. Graft-versus-host disease. Nat Rev Immunol 2007;7(5):340-52.
[5] van den Brink MR, Burakoff SJ. Cytolytic pathways in haematopoietic stem-cell trans-
plantation. Nat Rev Immunol 2002;2(4):273-81.
[6] Welniak LA, Blazar BR, Murphy WJ. Immunobiology of allogeneic hematopoietic stem
cell transplantation. Annu Rev Immunol 2007;25:139-70.
Search WWH ::
Custom Search