Table 2.
Humanization of TNF/LT system in mice as a tool to study human hematopoiesis.
| Humanized mouse line | Expression specificity | Hematopoiesis-unrelated phenotype | Hematopoiesis-related phenotype | References | |
|---|---|---|---|---|---|
| hTNF Tg (Tg197) | High copy number |
Systemic | Severe polyarthritis as early as 3-4 weeks after birth Spontaneous spanial disc herniation |
Mild microcytic hypochromic anemia Decrease in frequency of Sca1+ progenitor cells and granulocytes Increased frequency of lymphoid and monocytic origin in the bone marrow |
(83–85) |
| Low copy number |
Systemic | Progressive arthritis at a later age Reduced body weight Increased metabolic rate Restricted motor activity |
(86) | ||
| ihTNFtg | Doxycycline-inducible | Systemic | Psoriatic arthritis Keratinocyte activation Joint and skin inflammation |
(87) | |
| CD2-TNF | T cell | Progressive weight loss Vascular thrombosis Tissue necrosis Lymphoid tissue abnormalities Reduced thymic cellularity Enlarged mesenteric lymph nodes almost without lymphocytes |
(88) | ||
| GFAP-wtTNF | Astrocytes | Lethal neuroinflammation Ataxia, imbalances, seizures, relapsing hind limb paralysis Diminished weight gain |
(89) | ||
| GFAP-tmTNF | Severe neuroinflammation Complete hind limb paralysis Normal weight gain |
||||
| NFL-wtTNF | Neurons | Severe neuroinflammation Hind leg paralysis |
|||
| NFL-tmTNF | No abnormalities | ||||
| hTNF/LT Tg | Systemic | Thymic atrophy Impaired transition of DN1 thymocytes to the DN2 |
(90) | ||
| hTNFR1 Tg | Systemic | Prophylactic administration of TNFR1 antagonist leads to EAE amelioration and delayed disease onset | (91) | ||
| hTNFKI | Systemic | Pharmacological TNF inhibition with Etanercept, Infliximab and Adalimumab inhibits germinal center formation upon SRBC immunization Pharmacological TNF neutralization with Infliximab results in loss of mycobacterial infection resistance in M. tuberculosis infection Pharmacological TNF inhibition with Etanercept or Infliximab reduces transplantable tumor growth of MCA205 fibrosarcoma and MDSC accumulation Pharmacological TNF neutralization with Infliximab protects mice from collagen antibody-induced arthritis Exacerbated disease and decreased Treg numbers in EAE |
Pharmacological TNF inhibition decreases differentiation of CD11b+ cells into Ly6C+ monocytes and expression of genes encoding anti-apoptotic proteins in vitro | (82, 92–95) | |
| hTNF x hTNFR2KI | Systemic (with the option of Cre-mediated hTNFR2 deletion in specific cell type) | Disease score and Treg numbers comparable to wild type mice in experimental autoimmune encephalomyelitis hTNFR2 deletion in FoxP3+ Tregs results in EAE exacerbation and malfunction of Tregs |
(95) | ||
| hu/mTNFR1-k/i | Systemic | Treatment with TNFR1 antagonist protects cholinergic neurons against cell death and improves memory performance in a model of NMDA-induced neurodegeneration Treatment with TNFR1 antagonist inhibits EAE development and demyelination |
(96, 97) | ||
| hu/mTNFR2-k/i | Systemic | Treatment with TNFR2 agonist protects cholinergic neurons against cell death and improves memory performance in a model of NMDA-induced neurodegeneration | (96) | ||