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Translational and clinical advances in aGvHD
ing of transplant biology, briefly outlined below.
In the initial host tissue injury phase, exogenous and endogenous antigens classified as sterile damage-associated molecular patterns (DAMP; e.g., uric acid, ATP, heparan sul- fate, HMGB-1 or IL-33) and pathogen-associated molecular patterns (PAMP; e.g., bacterial lipopolysaccharides) interact with antigen-presenting cells (APC) in the innate and adap- tive immune systems, with activation of cytokine cascades (IL-1, IL-6, TNF-a, etc.) that set the stage for T-cell priming
and expansion.1
The second phase involves Teff trafficking (mediated by
L-selectin, CCR7, etc.) to lymphoid organs and host tissues. CD8+ and CD4+ Teff cells homing to the gut express high levels of integrin β7 (a4β7) which bind corresponding host tissue ligands. At their destination, Teff activation via APC- mediated host tissue:TCR interaction is initiated. This step, modulated by anti- versus co-stimulatory pathways and cytokine cascades, finally leads to the third phase, self- potentiating Teff cell proliferation and activation causing tissue damage via direct cellular cytotoxicity and indirectly via release of soluble mediators (TNF-a, IFN-γ, IL-1 and nitric oxide).3 The canonical NOTCH pathway is involved in regulating GvHD pathogenesis4 and using humanized monoclonal antibodies, it was shown that Notch-deprived T cells (with predominant roles for NOTCH1 and Dll-4) produce less inflammatory cytokines but proliferate nor- mally, with a preferential increase in regulatory T cells (Tregs), without compromising GvL.5 Selective NOTCH blockade offers potential for clinical translation.
Such immune activation is opposed by anti-inflamma- tory Tregs, a T-cell subset important in immunologic tol- erance, in part via release of anti-inflammatory cytokines such as IL-10 and TGF-β.6 Additionally, the balance of effector T-helper (Th) type 1 (IL-2, INF-γ) and type 2 (IL- 4, IL-10) cytokine responses may govern the ultimate out- comes of inflammation since type 2 cytokines can inhibit potent proinflammatory type 1cytokines, and a Th1 to Th2 shift could be beneficial in aGvHD.7 A distinct subset of CD4+ cells (characterized by production of IL-17A and F, IL-21 and IL-22) called Th17 cells has also been identi- fied, which in murine models migrate to GvHD target organs causing severe pulmonary and GI lesions and GvHD lethality,8 and may play a critical role in GvHD pathogenesis9 antagonistic to Tregs. Invariant natural killer T (iNKT) cells (discussed below) are another cellular subset with putative immunoregulatory functions, in part via an increase in Treg numbers and IL-4 secretion, that may be important in GvHD pathophysiology.
Here we discuss novel advances in the prevention and therapy of aGvHD built on the understanding of these concepts.
Acute graft-versus-host disease prevention Established determinants of acute graft-versus-host
disease
The well-established impact of conditioning regimen intensity, donor-recipient HLA-mismatch and graft source (bone marrow [BM], peripheral blood stem cell [PBSC]) on aGvHD outcomes is briefly discussed below.
Conditioning regimen intensity - the impact of conditioning intensity on aGvHD is primarily due to tissue damage- induced DAMP/PAMP release (see above). In general, mye- loablative conditioning (MAC) (particularly total body irra-
diation [TBI])-containing regimens are associated with higher aGvHD rates, an effect more pronounced with PBSC grafts.10 Non-myeloablative (NMA) and reduced-intensity conditioning (RIC) transplants have been associated with lower aGvHD rates11,12 than MAC, and even the newer reduced-toxicity regimens (e.g., ablative busulfan/fludara- bine) as per a large randomized controlled trial (RCT).13 There has, therefore, been a shift towards minimizing TBI except when absolutely necessary (e.g., acute lymphoblas- tic leukemia).
Novel therapeutic targeting of DAMP/PAMP:immune cell interactions are being investigated. For example, ATP (a DAMP) interacts with APC to activate inflammatory STAT1 signaling. Interruption of this pathway reduced GvHD in murine models14 although translation into clinical practice is still awaited.
Donor-recipient human leukocyte antigen (HLA)-mismatch - HLA-mismatch is an aGvHD risk factor. Large registry stud- ies document increased aGvHD rates (including severe aGvHD grades III-IV) and impaired survival for 1-2 locus HLA-mismatch versus 8 of 8 HLA-matched MAC and RIC HSCT.15,16 With the advent of post-transplant cyclophos- phamide (PTCy)-based regimens, the effect of HLA-mis- match may be less deleterious. PTCy was initially intro- duced in haploidentical (haplo) HSCT, but in a trial of matched and single-antigen mismatched unrelated donors (MUD, MMUD) it was found superior to standard CNI- based prophylaxis (discussed below).17 The role of PTCy in single-antigen MMUD HSCT is being further explored, with one study showing better rates of acute and chronic GvHD, non-relapse mortality (NRM), and relapse with PTCy compared to anti-thymocyte globulin (ATG).18 Many centers are adopting a PTCy-based platform for MUD/MMUD HSCT.
Graft source - while unmanipulated donor BM grafts were initially used in transplantation, there is now a sec- ular trend towards use of PBSC grafts, due to logistical reasons and donor preference. In a large meta-analysis comparing the two graft sources, there was no difference in overall aGvHD rates, although severe grade III-IV aGvHD and chronic severe GvHD was lower with BM. However, relapse in that analysis appeared higher with BM grafts leading to impaired disease-free survival (DFS) and overall survival (OS) in late stage disease.19 In a phase III RCT of MUD PBSC versus BM HSCT, OS was similar (albeit with relatively short follow-up) with no differ- ences in aGvHD or relapse, but chronic GvHD rates were lower with BM.20 Hence BM is arguably the better graft source, although the effect on relapse needs longer term follow-up. Cord blood transplants have resulted in similar rates of aGvHD as conventional sources although with lower rates of cGvHD.21 It should be mentioned that many GvHD prophylaxis regimens have been tested in association with specific stem cell sources making the interpretation of these data difficult.
Innovations in acute graft-versus-host disease prophylaxis
Since the cardinal events in aGvHD etiopathogenesis involve T-cell trafficking, interaction with host antigens and activation to cause tissue injury, the cornerstone of aGvHD prevention remains depletion or modulation of donor T
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