Page 1864 - Hematology_ Basic Principles and Practice ( PDFDrive )

1656 Part X Transplantation

TABLE T Cell–Antigen-Presenting Cell Interactions perforin-mediated GVL in an IFN-γ dependent manner. 178–180 Recent
108.3 clinical data suggest that enhancing recipient NKT cells by repeated
TLI conditioning promoted Th2 polarization and dramatically
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T Cell APC reduced GVHD. Experimental data also show that activated donor
Adhesion NK cells can reduce GVHD through the elimination of host APCs
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ICAMs LFA-1 or by secretion of transforming growth factor-β (TGF-β). A murine
LFA-1 ICAMs BMT study using mice lacking SH2-containing inositol phosphatase,
CD2 (LFA-2) LFA-3 in which the NK compartment is dominated by cells that express two
CD 226 (DNAM-1) CD155, CD112 inhibitory receptors capable of binding either self or allogeneic MHC
ligands, suggests that host NK cells may play a role in the initiation
Recognition of GVHD. 181
TCR/CD4 MHC II
TCR/CD8 MHC I
Costimulation T-Cell Apoptosis and Signaling
CD28 CD80/86
CD152 (CTLA-4) CD80/86 Deletional mechanisms of tolerance fall into two categories: (1)
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ICOS B7H/B7RP-1 central (thymic) deletion and (2) peripheral deletion. Central dele-
PD-1 PD-L1, PD-L2 tion is an effective way to eliminate continued thymic production of
Unknown B7-H3 alloreactive T cells. To this end, lymphoablative treatments have been
CD154 (CD40L) CD40 used as a condition to create a mixed hematopoietic chimeric state
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CD134 (OX 40) CD134L (OX40L) in murine BMT models. In this strategy, donor cells seed the
CD137 (4-1BB) CD137L (4-1BBL) thymus and maturing donor-reactive T-cell clones are deleted through
184,185
HVEM LIGHT intrathymic apoptosis. The pathways of T-cell apoptosis by
which peripheral deletion occurs can be broadly categorized into
APC,Antigen-presenting cell; CTLA-4, cytotoxic T lymphocyte antigen 4; activation-induced cell death (AICD) and passive cell death (PCD).
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DNAM-1, DNAX accessory molecule-1; HVEM, HSV glycoprotein D for 187
herpesvirus entry mediator; ICAM, intercellular adhesion molecule; L, ligand; An important mediator of AICD in T cells is the Fas receptor.
LFA, leukocyte function–associated antigen; LIGHT, homologous to Activated T cells expressing the Fas molecule undergo apoptotic cell
lymphotoxins, shows inducible expression, and competes with HVEM, a death when brought into contact with cells expressing Fas ligand. A
receptor expressed by T lymphocytes; MHC, major histocompatibility complex; critical role for Fas-mediated AICD has been clearly demonstrated in
PD, programmed death; TCR, T-cell receptor.
attenuation of acute GVHD by several type 1 T helper (Th1) cyto-
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kines. PCD, or “death by neglect,” illustrates the exquisite depen-
dence of activated T cells on growth factors (e.g., IL-2, IL-4, IL-7,
and/or IL-15) for survival; apoptotic cell death in this instance is
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not the case for the memory (CD62L ) T cells across different donor/ largely because of rapid downregulation of B-cell lymphoma 2. 188–190
recipient strain combinations. 150–153 Furthermore, expression of naive Transplantation of B-cell lymphoma-extra large T cells into nonir-
T-cell marker CD62L was also found to be critical for regulation of radiated recipients significantly exacerbates GVHD; however, no
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GVHD by donor natural regulatory T cells. By contrast, another difference in GVHD mortality is observed in animals that have been
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recent study demonstrated that alloreactive memory T cells and their lethally irradiated. Selective elimination of donor T cells in vivo
precursor cells (memory stem cells) caused robust GVHD. 155,156 after BMT using transgenic T cells in which a thymidine kinase (TK)
suicide gene is targeted to T cells has also been shown to attenuate
Regulatory T Cells the severity of acute GVHD. 191–194 Another recent approach to
Recent advances indicate that distinct subsets of regulatory prevent GVHD is the selective depletion of alloantigen-specific
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CD4 CD25 , CD4 CD25 IL10 Tr cells, γδT cells, DN T cells, donor T cells by a photodynamic cell-purging process, wherein donor
NKT cells, and regulatory DCs control immune responses by induc- T cells are treated with photoactive 4,5-dibromorhodamine 123 and
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tion of anergy or active suppression of alloreactive T cells. 97,98,157–165 subsequently exposed to visible light. Targeting alloreactive T-cell
Several studies have demonstrated a critical role for the natural donor bioenergetics has emerged as a newer strategy to mitigate GVHD in
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CD4 CD25 Foxp3 regulatory T cells (Treg), obtained from naive mice. 196,197 Thus several deletional mechanisms have been shown
animals or generated ex vivo, in the outcome of acute GVHD. Some to reduce acute GVHD but the conditions under which one or
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studies have demonstrated that donor CD4 CD25 T cells suppressed another of these deletional mechanisms predominate remain to be
the early expansion of alloreactive donor T cells and their capacity to determined.
induce acute GVHD without abrogating GVL effector functions, APC and T-cell activation results in rapid intracellular biochemi-
while others have shown that depending on the tumors used and the cal signaling cascades that activate or negatively regulate alloreactive
context, GVL may be reduced as well. 166–168 The mechanisms by donor T-cell responses. The calcineurin-nuclear factor of activated
which donor Tregs suppress GVHD are being better understood. The T cell (NFAT) pathway has been shown to be an effective target for
presence of signal transducer and activation of transcription (STAT)1 mitigating GVHD and forms the bedrock of clinical care. Specifically,
signaling has been shown to enhance Treg-mediated suppression of the calcineurin inhibitors cyclosporine and tacrolimus. Cyclosporine
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GVHD. A key role for host APCs in the induction of GVHD binds to the cytosolic protein peptidyl prolyl cis-trans isomerase A
protection, and for donor APCs in the sustenance of the protection (also known as cyclophilin), whereas tacrolimus binds to the peptidyl-
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by the infused mature Tregs has been demonstrated. Several small prolyl cis-trans isomerase FK506-binding protein (FKBP)12, and
clinical trials that either include expanding Tregs in vivo with IL-2, these complexes (cyclosporine–cyclophilin or tacrolimus–FKBP12)
or by epigenetic targeting of histone acetylation at the Foxp3 locus, inhibit calcineurin, thereby blocking the dephosphorylation of NFAT
198
or by preferential expansion of Tregs by cyclophosphamide have and its nuclear translocation. These events prevent NFAT from
shown clinical benefit in early phase II trials. 171–174 Direct infusion of exerting its transcriptional function, resulting in the inhibition of
ex vivo expanded donor Tregs has also demonstrated potential clinical transcription of IL-2 and of other cytokines and ultimately leading
benefit in small early phase trials and several clinical trials are under- to a reduced function of T-cells and mitigation of GVHD. Merging
way in the United States and Europe with attempts to substantially data have identified several key T-cell signaling pathways, many of
expand these cells ex vivo and use for prevention of GVHD. 175,176 which are being targeted in the clinic. Notably, the mammalian
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Host NK1.1 T cells are another T-cell subset that has been shown target of rapamycin (mTOR) pathway has been shown to be critical
to suppress acute GVHD in an IL-4 dependent manner. 164,165,177 By for blocking IL-2–mediated signal transduction and prevents cell-
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contrast, donor NKT cells were found to reduce GVHD and enhance cycle progression in naive T cells. Inhibition of mTOR with