. Author manuscript; available in PMC: 2024 Jun 3.

Published in final edited form as: Nat Rev Immunol. 2023 Dec 12;24(5):338–357. doi: 10.1038/s41577-023-00970-x

Table 1 ∣.

Antigen-specific immunotherapy approaches

Material	Mediator of antigen specificity	Immunomodulator	Disease model	Findings	Refs.
Cell-based approaches
IL-10-moDCs	Lentiviral vectors		NOD	Induction of antigen-specific T cell tolerance and prevention of disease	122
Schwann cells+ PEG–PLGA NPs	Natural	PD-L1–Fc, CD86–Fc, leflunomide	EAE	Inhibition of T_H1 cell responses, leflunomide loading increased myelin repair	256
Erythrocytes	Peptide mimotope		NOD	Reduced trafficking of effector T cells into organs	136
Erythrocytes	Recombinant antigen		EAE	Persistent antigen exposure via erythrocytes induced T cell exhaustion and dysfunction	135
BAR T_reg cells	Retroviral		ADAs	ADA suppression	146
CAR T_reg cells	Retroviral		EAE	Suppression of antigen-specific and other T cells even in a pro-inflammatory environment	147
CAR T_reg cells	Plasmid		Allograft rejection	Protection of allografts better than polyclonal Treg cells	142
CAR/FOXP3⁺ T_reg cells	CAR		EAE	Intranasally administered cells accessed various brain regions and suppressed disease	144
Vitamin D3–IL-4–IL-10–GM-CSF moDCs	None	CTLA4–Ig	Alloimmune reactivity	Only in addition with CTLA4–Ig: alloreactive T_reg cell induction and reduction in T cell activity	126
Apoptotic cells	Peptide	CFA	Arthritis	Induction of antigen-specific tolerance via B cell-mediated T_reg cell induction	134
Viral-based approaches
Cowpea mosaic virus	Plasmid		EAE	Safe and efficient gene delivery	220
Adeno-associated virus	Plasmid		EAE	Liver-targeted expression of protein induced T_reg cells, regardless of epitope or HLA background	219
Lentivirus	Plasmid		NOD	Transient expression of antigen with integrase-incompetent lentivirus protected from disease	217
Nanoparticles without adjuvant
PLGA NPs			EAE, DTH	Tolerance dependent on dose and antigen loading	157
PLGA NPs	Multiple proteins		NOD	Encapsulation of multiple epitopes broadened spectrum of induced tolerance	257
PEMA-PLGA NPs	Protein		EAE	Kupffer cells and LSECs induced tolerance after antigen uptake	194
Liposome	mRNA		EAE	Bystander tolerance by induction of T_reg cells	237
Modified PLGA NPs	Peptide		EAE, NOD, colitis	Optimized NPs can be effectively loaded with a variety of antigens	258
PEG–PLGA NPs	Peptide		EAE	PEGylation increased bioavailability of subcutaneously injected NPs	192
Iron oxide NPs	MHC class II-bound ubiquitous antigen		EAE	Ubiquitous liver autoantigens are involved in extrahepatic immune diseases and tolerance induction mitigates extrahepatic autoimmunity	259
PEGylated iron oxide NPs	MHC class II-bound peptide		PBC, AIH, PSC	Ubiquitous antigens are involved in autoimmune liver diseases	260
PLGA NPs	Hybrid peptide		NOD	Effector T cell anergy induced against several epitopes	154
PLGA NPs	Peptides		NOD	Antigen-coupled NPs induced T_reg cells	155
DSPG liposomes	Peptide		Atherosclerosis	C1q-dependent update via scavenger receptors induced tolerance	173
PLGA NPs	Peptide		R-EAE	Uptake of antigen by APCs led to PD-L1-dependent tolerance induction	182
CdSe-ZnS-quantum dots	Protein		EAE	Antigen density dictates disease suppression	158
Dextran-coated or PEGylated iron oxide	MHC class II-bound peptide		EAE, NOD	Expansion of T_R1 cells	149
PSL NPs	None		Atherosclerosis	Apoptotic cell mimicry induced IgM and reduced inflammation	181
PLGA-PEMA NPs	Protein		R-EAE	Surfactant modification increased efficacy of NPs, reduced CNS infiltration of effector T cells	156
PEI NPs	Plasmid		Arthritis	Reduction of TLR9 activation by DNA promoted IDO-mediated induction of tolerance	261
Iron oxide NPs	MHC class I-bound peptide		NOD	Induction of T_reg cells that suppressed APCs via IDO and perforin	198
Dendrimer branched lysine core particles	Multiple antigen peptides		EAE	Non-inflammatory presentation of antigen decreased effector T cell but not T_reg cell CNS infiltration	262
Peptide–polymer	Peptide		Cholangitis	LSECs presented antigen on MHC class I, decreasing liver infiltration of antigen-specific CD8⁺ T cells	263
Particles with adjuvant
PLGA NPs	Peptide	ICAM1 inhibitor	EAE	Dual-peptide NPs have stronger inhibitory effect	264
Dual size PLGA	Protein	GM-CSF, TGFβ, vitamin D3	NOD	Long-lasting protection in advanced disease states	210,211
Liposomes/serum-albumin–bound NPs	Protein	T_reg cell epitopes	NOD	Tregitopes induced tolerance via specific T_reg cell activation	265
Lipid-coated salt NPs	Citrullinated peptides	Rapamycin	RA	Induction of immune tolerance in advanced disease	213
PEG–PLGA NPs	Peptide	Knockdown of CD40, CD80, CD86	NOD	Expansion of antigen-specific T_reg cells	266
Liposomes	Mimotope	Vitamin D3	NOD	Co-encapsulation of vitamin D3 can mediate bystander tolerance	214
Liposomes	Peptide	ITE	EAE	Co-encapsulation of immunomodulator induced T_reg cells and bystander tolerance	104
Liposomes	Peptide	Vitamin D3	RA, Goodpasture’s vasculitis	Calcitriol-antigen loaded NPs increased T_reg cells and suppressed effector T cells in a PD-L1-dependent manner	206
Liposomes	Peptide	CD22 ligands, rapamycin	Hypersensitivity	Rapamycin enhanced tolerance induction in naive but not in presensitized mice	208
PEG–Gold NPs	Peptide	ITE	EAE, NOD	Co-encapsulation of immunomodulators expanded T_reg cells and increased efficacy	102,103
PEG–PLA NPs, PLGA NPs	Peptides/drug	Rapamycin	EAE, DTH, ADAs	Co-encapsulation of rapamycin induced durable B and T cell tolerance	202
Dextran NPs	Peptide	Dexamethasone	EAE	Immunomodulator increased effectiveness	267
PLGA NPs	Peptide	Recombinant IL-10	EAE	NPs release antigen and immunomodulator constantly for several weeks, addition of IL-10 decreased IL-17 and IFNγ	205
PEG–liposomes	Multivalent peptide	CD22 ligands	ADAs	Tolerance induction towards presented alloantigen	268
Liposomes	Protein	NF-κB inhibitors	RA	Co-encapsulation of immunomodulators increased efficacy of tolerance induction	203
Particle free
Anti-MHC class II antibodies	Peptide	Dexamethasone	EAE, NOD, RA	Immunomodulator reduced adverse effects and increased effectiveness	207
Nanoemulsion	Citrullinated self-antigen	Rapamycin	RA	Nanoemulsion accumulated in inflamed regions and suppressed disease activity	207
Mannosylated antigen	Peptide		EAE, R-EAE	Amelioration of EAE, reduced CNS infiltration of immune cells	196

ADA, antidrug antibody; AIH, autoimmune hepatitis; APC, antigen-presenting cell; BAR, B cell-targeting antibody receptor; CAR, chimeric antigen receptor; CFA, complete Freunds adjuvant; CNS, central nervous system; CTLA4, cytotoxic T lymphocyte associated protein 4; DC, dendritic cell; DSPG, 1,2-distearoyl-sn-glycero-3-phosphoglycerol; DTH, delayed-type hypersensitivity; EAE, experimental autoimmune encephalitis; ICAM1, intercellular adhesion molecule 1; IFNγ, interferon-γ; GM-CSF, granulocyte-monocyte colony-stimulating factor; IDO, indoleamine-pyrrole 2,3-dioxygenase; LSECs, liver sinusoidal endothelial cells; moDC, monocyte-derived dendritic cell; NF-κB, nuclear factor-κB; NOD, non-obese diabetes; NP, nanoparticle; PBC, primary biliary cholangitis; PD-L1, programmed cell death ligand 1; PEG, polyethylene glycol; PEI, polyethyleneimine; PEMA, poly(ethylene-maleic acid); PLA, poly(lactic acid); PLGA, poly(lactic-co-glycolic acid); PSC, primary sclerosing cholangitis; PSL, phosphatidyl serine liposome; RA, rheumatoid arthritis; R-EAE, relapsing–remitting EAE; TGFβ, transforming growth factor-β.