Table 4.

Summary of chronic GVHD mouse models

Model Type	Model Characteristics	Model Clinical Phenotype	Findings	Therapies generated	Ref.
Lupus-like	parental (P) haploidentical, DBA2 (H-2d haplotype) splenocytes into un-conditioned (B6 X DBA2) F1 hosts (H-2bd haplotype)	DNA and chromatin–directed auto-antibody; immune-complex-mediated glomerulonephritis lack of clinical correlation to human chronic GVHD	partial donor chimerism relies on activated host B-cells	CD137 agonist therapy anti-TNF p55 subunit blockade	(300, 301)
Thymic damage	Acute GVHD in lethally irradiated, MHC-mismatched, recipient. Post-BMT splenic T cells transferred into unconditioned donor strain immune-deficient (Rag−/−) recipients	Inflammatory disease (colitis) Not a fibrotic process	GVHD is antigen-driven repertoire skewing seen dominant high-frequency clonotypes		(69, 129, 302)
Multi-organ involvement	MHC disparate model, B10.BR mice are conditioned with cyclophosphamide and TBI followed by the infusion of BM and purified splenic T cells from B6 donors	Multi-organ involvement Lung Liver Colon Tongue Spleen Thymus	CD4+ T cell and B cell infiltration in target organs Increased frequency of T follicular helper (Tfh) cells by supporting GC formation and maintenance leading to IgG deposition in target tissues are essential for disease pathogenesis Deficiency of T follicular regulatory cells that suppress GC formation Macrophage dependent disease Multi-organ system fibrosis (lung, liver, colon) is a prominent feature of disease	Abrogation of chronic GVHD by targeting: Lymphotoxin-beta receptor immunoglobulin targeting GC formation B-cell signaling through Bruton’s tyrosine kinase (BTK) and IL2 inducible T-cell kinase (ITK) via ibrutinib; Spleen tyrosine kinase (Syk) targeting with fostatinib Targeting Tfh cells by blocking ICOS, CD40L, IL21, IL2Rgc Phosphorylation of STAT3, Rho-associated kinase 2 (ROCK2), RORC, Jak1/2 (ruxolitinib) Macrophage depletion by targeting CSF1 signaling T follicular regulatory infusion	(98, 132, 144, 217, 240, 241, 252, 273, 310)
Sclerodermatous/Lupus-like	DBA/2 (H-2d) and BALB/c (H-2d) minor antigen only-mismatched sub-lethal irradiation and DBA/2 splenocytes	Donor B and CD4+ T cells are required for pathogenesis	B cells drive clonal donor autoreactive CD4+ T cells CD11b+/Gr-1+ PMN & macrophages	Anti-CD20 antibody prevents chronic GVHD	(295, 336).
Pro-fibrotic	Classical model B10.D2→BALB/c Donor T cells B10.D2 and BALB/c mice are MHC matched (H-2d haplotype) mismatched at MiHA 700cGy of TBI to recipients and infusion of BM and whole spleen cells	Fibrotic changes skin gastrointestinal tract liver BOS model donor B and CD4+ T cells are required for pathogenesis	Mononuclear cell Infiltration, increased collagen deposition Expansion of Th1 and Th17 cells, derma fibrosis with donor-CD11b+ monocytes & activated macrophage Effector T-cells and pSTAT3 dependent IL-10 producing B cells prevent disease	Prevention and/or attenuation of established chronic GVHD Am80, a potent synthetic retinoid sphingosine-1-phosphate receptor antagonist FTY720 modulates inflammatory immune cells Bortezomib modulates pathogenic B cells	(136–138, 144, 249, 304–307, 336)
Sclerodermatous	LP/J→C57BL/6 model of sclerodermatous chronic GVHD HLA-matched strains Myeloablative	Manifestations of both acute and chronic GVHD Skin Lungs Kidney	Removal of B cells prevents T cell priming to MiHA and development of chronic GVHD	Prevention of chronic GVHD Treatment with anti-μ polysera Chloroquine Ibrutinib	(241, 308)
Inflammatory with progression of acute GVHD to chronic GVHD	MHC mismatched, strain combination (B6 → Balb/c) established model of acute GVHD Reducing donor T cells develop pathognomonic findings of chronic GVHD (>60 days after HCT)	Chronic GVHD manifestation cutaneous fibrosis salivary glands fibrosis of the thymus serum auto-antibodies	Donor CD4+ and CD8+ alloreactive T-cells damage mTECs Donor CD8+ T-cells induce chronic GVHD Recipient thymus and de novo donor CD4 T cells required IL-17 mediates scleroderma skin Macrophages critical	targeting CSF-signaling	(70, 159, 295).
Progressive acute GVHD to chronic GVHD	C57Bl/6 parent →irradiated B6D2F1 model with BM + G-CSF mobilized splenocytes or un-mobilized, T cells	Sclerodermatous manifestation of chronic GVHD: skin lung	TNFα important for progression acute GVHD to chronic GVHD of the lung	Anti-CSF-1 Anti-TNFα (Etanercept)	(132, 292, 296)