Harnessing and honing mesenchymal stem/stromal cells for the amelioration of graft-versus-host disease

Table 1 Immunosuppressive effect exerted by mesenchymal stem/stromal cells from different sources on immune cells

MSC types	Mechanism of immunosuppressive effect	Ref.
BM-MSCs	Recipient-derived MSCs from patients with GVHD are analogous to MSCs from healthy volunteers	Copland et al[47]
	After MSC infusion, the ratio of Th1 cells to Th2 cells was reversed, with an increase in Th1 and a decrease in Th2 achieving a new balance	Zhou et al[48]
	BM-MSCs reduce the incidence and severity of GVHD by improving thymic function and induction of Tregs but not increase the risks of infections and tumor relapse	Zhao et al[49]; Selmani et al[50]
	HLA-G5 secreted by MSCs is critical to the suppressive functions of MSCs	Selmani et al[51]
MenSCs	MenSCs exhibit a higher capacity to migrate into the intestine and liver and not to their anti-inflammatory capacities	Luz-Crawford et al[52]
FL-MSCs	FL-MSCs demonstrates much longer-lasting immunomodulatory properties by inhibiting directly the proliferation and activation of CD4+ and CD8+ T cells	Yu et al[53]
UC-MSCs	UC-MSCs showed minimal expression of HLA-DR after activation and posed minimal risk of initiating an allogeneic immune	Kim et al[54]
	UC-MSCs alleviate SLE through upregulating Treg cells, which was partly dependent on HLA-G	Chen et al[55]
	UC-MSCs ameliorate GVHD and spare GVL effect via immunoregulations	Wu et al[56]
WJ-MSCs	WJ-MSCs exert immunosuppressive effects by cell-cell contact with activated T cells and in part through the soluble factor indoleamine 2,3-dioxygenase	He et al[57]
MC-, WJ- and BM-MSCs	The mixed populations of MSCs displayed all of the positive attributes of WJ-MSC and BM-MSC	Mennan et al[58]
AT-MSCs	The use of AT-MSC rather than BM-MSC could further preserve NK cell activity and favor GVL	Blanco et al[59]
hG-MSCs	hG-MSC treatment inhibited local inflammation of injured skin by suppressing inflammatory cells, reducing pro-inflammatory cytokine tumor necrosis factor-α, and increasing anti-inflammatory cytokine interleukin-10, which was promoted by hypoxia	Jiang et al[60]
CP-, BM- and AT-MSCs	CP-MSCs may have additional advantage over the other MSCs in terms of immunomodulation	Lee et al[61]
DP-MSCs	Immunomodulation and expression of trophic factors by dental MSCs increase their resistance to allogeneic NK cell lysis and their potential in vivo lifespan	Martinez et al[62]

AT: Adipose tissue; BM: Bone marrow; CP: Chorionic plate; DP: Dental pump; FL: Fetal liver; hG: Human gingiva; GVHD: Graft-versus-host disease; GVL: Graft-versus-leukemia; MenSC: Menstrual blood-derived mesenchymal stem cell; MSC: Mesenchymal stem cell; UC: Umbilical cord; WJ: Wharton jelly.

Table 2 Effects of different mesenchymal stem/stromal cells on refractory acute graft-versus-host disease

Study type	Patient No.	Indication	MSC type	Response criteria	Main findings	Ref.
Phase 2	55	Steroid-resistant, severe, aGVHD	BM	Glucksberg	CR: 30/55, better OS/TRM for complete responder	Le Blanc et al[63], 2008
Phase 2	31	Gr. II-IV aGVHD	BM	Glucksberg	CR: 77%; PR: 16%	Kebriaei et al[64], 2009
Pilot study	20	Co-transplantation with NMA mismatched HSCT	BM	Glucksberg	Decreased 1 yr GVHD death (10% vs 31%, P = 0.04). Better NRM & OS	Baron et al[65], 2010
Retrospective	37	Resistant Gr. III-IV aGVHD	BM	Glucksberg	CR: 65%, better TRM and OS	Ball et al[66], 2013
Multicenter trial	50	Resistant Gr. IV aGVHD	BM	Not mentioned	OR: 33%, CR: 17%, initial response and young age have better survival	Resnick et al[67], 2013
Prospective, single-arm, open-label	75	Severe refractory aGVHD	BM	IBMTR SI	OR on day +28: 61.3%, better OS for responder on day +100 (78.1% vs 31.0%; P < 0.001)	Kurtzberg et al[68], 2014
Phase 1	40	Resistant Gr. II-IV aGVHD	BM	Glucksberg	CR: 27.5%, OR: 67.5% on day +28; more CR in pediatric group	Introna et al[69], 2014
Phase 2	25	Refractory aGVHD	BM	Glucksberg	71% responded, CR 11/24, better OS for CR	Sánchez-Guijo et al[70], 2014
Prospective, nonrandomized	28 vs 19 without MSC	Refractory aGVHD	BM	Glucksberg	Decreased incidence and severity of cGVHD. Better OR and CR.	Zhao et al[49], 2015
Phase 2	48	Steroid-resistant aGVHD	BM	Glucksberg	CR: 25% on day 28, 50% lasting > 1 mo, with better OS	Te Boome et al[71], 2015
Compassionate use	58	Steroid-resistant aGVHD	BM	IBMTR SI	OR: 47%, but no improvement in OS	von Dalowski et al[72], 2016
Phase 2/3	25	Refractory Gr. III-IV aGVHD	BM	Glucksberg	Better OS for OR at 4-wk (CR: 6/25, PR: 9/25)	Muroi et al[73], 2016
Pilot study	33	Refractory aGVHD	BM	IBMTR SI	CR: 18/33, PR: 7/33, better OS in CR, no TRM in CR	Erbey et al[74], 2016
Compassionate use	26	Severe resistant aGVHD	BM	Not mentioned	OR: 77% on day +28 (CR: 5/26, PR: 15/26)	Kuçi et al[75], 2016
Phase 2 prospective RCT	62 vs 62 without MSC	cGVHD prophylaxis in haplo	Cord	NIH score	cGVHD: 27% (MSC) vs 49% in 2 yr (P = 0.021)	Gao et al[76], 2016
Phase 1/2	26	Steroid-refractory aGVHD	BM	Glucksberg	OR: 62% on day 28. Higher response rate in children. High NRM in adults	Salmenniemi et al[77], 2017
Pilot study	22	Refractory GVHD (Gr. 2-4 a or cGVHD)	BM or adipose tissue	Glucksberg/NIH score	CR: 45.8%, PR: 33.3%, better OS in CR/PR	Cetin et al[78], 2017
Retrospective	46	Refractory Gr. III/IV aGVHD	BM	Not mentioned	50% responded with better OS (P = 0.0004)	Dotoli et al[79], 2017
Phase 1/2	33	Steroid-refractory aGVHD	BM	Glucksberg	CR: 34%, PR: 50% on day 28. Better OS on day 90 and 1 yr (P = 0.006, 0.002)	Fernández-Maqueda et al[80], 2017
Phase 1/2	69	Refractory aGVHD	BM	Glucksberg	OR: 83% on day 28	Bader et al[81], 2018
Observational study	34 vs 34 without MSC	aGVHD	BM or adipose tissue	IBMTR SI	Better OS compared with historical control, P = 0.0678. MSC has no association with risk of infectious complication	Stoma et al[82], 2018
Retrospective	11 (study group 2)	Severe refractory aGVHD	Placenta derived decidual stromal cell	Glucksberg	73% 1 yr OS in study group 2 (albumin), 47% in group 1 (AB plasma), P = 0.016	Ringden et al[83], 2018
Retrospective	22	Severe refractory aGVHD	Cord	IBMTR SI	CR: 45.5%, PR: 13.6%	Bozkurt et al[84], 2019
Phase 3 RCT	151 vs 72 placebo	Severe refractory aGVHD	BM	IBMTR SI	Difference of durable CR (lasting > 28 d) not achieved (35% vs 30%, P = 0.42); Pediatric pts had better OR (64% vs 23%, P = 0.05)	Kebriaei et al[85], 2020

aGVHD: Acute graft-versus-host disease; BM: Bone marrow; cGVHD: Chronic graft-versus-host disease; CR: Complete remission; IBMTR SI: International Bone Marrow Transplant Registry severity index; MSC: Mesenchymal stem/stromal cells; OS: Overall survival; PR: Partial remission; RCT: Randomized controlled trial.