Dendritic Cell-Based Approaches for Therapeutic Immune Regulation in Solid-Organ Transplantation

Table 1

Recent advances in DC biology, tolerogenic DCs, and pharmacological conditioning protocols.

	Authors	Reference
Tolerogenic DCs
Constitutive ablation of DCs breaks self-tolerance of CD4^+ T cells leading to fatal autoimmunity	Ohnmacht et al.	[19]
Tolerogenic DCs favor graft tolerance through interferon-𝛾 and Epstein-Barr virus-induced gene 3	Hill et al.	[20]
Tolerogenic DCs generated with immunosuppressive cytokines induce antigen-specific anergy and regulatory properties in memory CD4^+ T cells	Torres-Aguilar et al.	[21]
DC genealogy
DC and monocyte lineages originate from a common progenitor that gives rise to monocytes and committed DC progenitors, which give rise to lymphoid tissue DCs and nonlymphoid tissue DCs	Liu and Nussenzweig	[22]
DCs in mouse lymphoid organs in the steady state are monocyte independent and require Flt3L for their development. Other tissue may contain additional M-CSF-dependent monocytes	Steinman and Idoyaga	[23]
The differing origins of gut DCs may explain how the intestinal immune system manages to destroy harmful pathogens while tolerating beneficial bacteria	Laffont and Powrie	[24]
Comparative genomics reveals functional equivalences between human and mouse DC subsets	Crozat et al.	[25]
Plasmacytoid DCs (pDCs)
Compared to conventional DCs, pDCs show reduced costimulatory molecule expression and poor T-cell allostimulatory capacity. Under homeostatic conditions, nonlymphoid tissue-resident pDCs regulate mucosal immunity and the development of both central and peripheral tolerance	Rogers et al.	[26]
Human pDCs preferentially express immunoglobulin-like transcript 7 (ILT7), which activates an immunoreceptor tyrosine-based activation motif- (ITAM-) mediated signaling pathway	Cao and Bover	[27]
Pharmacological DC conditioning
Rapamycin-conditioned, alloantigen-pulsed DCs present donor MHC class I-peptide via the semidirect pathway and inhibit survival of antigen-specific CD8^(+) T cells	Thomson et al. and Fischer et al.	[28, 29]
Human rapamycin-treated DCs are only partially maturation resistant in vivo	Macedo et al.	[30]
Adenosine A2AR agonist-conditioned DCs attenuate acute renal ischemia-reperfusion injury	Li et al.	[31]
Vitamin D3-conditioned DCs induce effector T-cell apoptosis and antigen-specific Tregs	Nikolic and Roep	[32]
Role of conventional DCs of the recipient in tolerogenic DC therapy
Depleting recipient DCs at the time of tolerogenic DC therapy abrogates its beneficial effect	Divito et al.,; Wang et al.	[33, 34]
Role of exosomes
Exosomes mediate transfer of functional microRNAs between mouse DCs	Montecalvo et al.	[35]
Exosomes from immature DCs plus rapamycin induce tolerance to mouse cardiac allografts	Li et al.	[36]
Clinical studies of tolerogenic DCs
Phase-1 trial of autologous tolerogenic DC therapy in patients with type-1 diabetes	Giannoukakis et al.	[37]
Clinical trials of tolerogenic DC therapy in patients with rheumatoid arthritis	Hilkens and Isaacs	[38]
OneStudy phase-1 trial of autologous tolerogenic DC therapy after kidney transplantation	Moreau et al.	[39]