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Table 1 Characteristics of the included studies

From: Immune responses to azacytidine in animal models of inflammatory disorders: a systematic review

Author first, last, year, journal

Species

Sex

Type of induction of disease

Aza or DAC

n/group

Dose

Dose regimen (frequency and timing)

Route of administration

Clinical outcome

Graft versus host disease (GvHD)

 

 Paluska Cihak 1982 Immunobiology*

Mice

M+F

Allogeneic splenocyte injection

Aza and DAC

8–17

6 or 20 mg/kg

24 h after splenocyte injection

IP

Decreased GvHD, depending on dosing

 Sula, Cihak, 1987, Czech Med

Mice

Unknown

Allogeneic splenocyte injection

Aza and DAC

5–10

5-25 mg/kg

Day -1, 0, 1, or 2 or multiple days

IP

Decreased GvHD, depending on dosing

 Sánchez-Abarca, Pérez-simon, 2010, the american society of hematology

Mice

M+F

BM transplantation + allogeneic splenocyte injection

Aza

5

1 mg/kg

after 60 and 84 h

IV

Decreased GvHD, increased survival

 Choi, Dipersio, 2010, the american society of hematology

Mice

Unknown

BM transplantation + allogeneic T cell injection

Aza and DAC

2–25

DAC: 1mg/kg , Aza: 2 mg/kg

Day 4, 6, 8, 10 after T cells

SC or IP

Decreased GvHD, increased survival

 Fransolet, Baron, 2016, Journal of hematology and oncology

Mice

M+F

BM transplantation + allogeneic splenocyte injection

Aza and DAC

3–16

DAC 0,75mg/kg, Aza 0,5 or 2 mg/kg

Day 10 2013Day 30, every 48 h

SC

Decreased GvHD, depending on dosing

 Cooper, DiPersio, 2017, Journal of immunology

Mice

M

BM transplantation + allogeneic T cell injection

Aza

3–10

2 mg/kg

Day 15, 17, 19 and 21

IP

Decreased GvHD, this is Treg dependent

 Ehx,Baron 2017 OncoImmunology

Mice

Unknown

Human PBMC injection (xeno–GvHD)

Aza

8–12

2 or 5 mg/kg

Day 1 – Day 21, every 48h

SC

Decreased GvHD, increased survival

Organ rejection

 Paluska Cihak 1982 Immunobiology*

Mice + Rats

M+F

Skin transplantation

Aza and DAC

4–11

6 or 20 mg/kg

Day -1, 1, 3, 5

IP

Prolonged graft survival, depending on dosing

 Cheng C, Xia J, 2014, Immunology

Mice

M#

Cardiac transplantation

Aza

3–6

1 mg/kg

Daily untill end of exp.

IP

Aza alone did not prolong graft survival

 Guo, Jiang, 2013, Transplant immunology

Mice

M

Cardiac transplantation

DAC

6

1,5 mg/kg

Day 1,2 and 3

IV

Prolonged graft survival

 Wang X, Tao, 2017, Oncotarget^

Mice

M

Cardiac transplantation

DAC

Unknown

0,25 or 0,5 mg/kg

Daily for 14 days

IP

Prolonged graft survival

 Uchida, Tisdale, 2014, PLOS ONE

Mice

M

Human stem cell transplantation (Xeno-rejection)

DAC

Unknown

0,5 μM (ex vivo)

48 h ex vivo prestimulation

Unknown

Prolonged graft survival

 Hong J, Yang, 2013, Transplant immunology

Mice

Unknown

Islet transplantation

Aza

6-9

1 mg/kg

Day 0 and 1

Unknown

Aza alone did not prolong graft survival

Diabetes

 Zheng, Zhao, 2009, J mol med

Mice

M+F

NOD mice + cyclophosphamide injection

DAC

5

0,1 or 0,15 mg/kg

Daily for 5 days or 5 weeks

IP

Prevented diabetes

 Wang, Shi, 2016, JCI insight

Mice

M

ob/ob mice + high fat diet

DAC

6–16

0,25 mg/kg

3x/week for 8 weeks

IP

Improved insulin sensitivity

 Gao, Mu, 2019, Stem Cell Research and Therapy

Mice

M

C57BL/6 mice + high fat diet + STZ

DAC

18

0,25 mg/kg

Daily for 5 days

IP

DAC alone did not improve clinical outcome

 Chen, Dong, 2019, Kidney international

Mice

M

db/db mice

DAC

6-9

1 mg/kg

2x/wk from week 8-20

IP

Improved diabetic nephropathy

 Zhang, Liang, 2017, Kidney International

Mice

M

db/db mice

Aza

6

1 or 2 mg/kg

3x/week for 8 weeks

IP

Improved diabetic nephropathy, no effect on blood glucose levels

Atherosclerosis

 Cao, Xua , 2014, Endocrinology

Mice

M

ldlr mice + High fat and cholesterol diet

DAC

8

0,25 mg/kg

3x/week up to 30 weeks

IP

Decreased Atherosclerosis Development

Biliary Arthresia

 Li, Tang, 2016, the american physiological society

Mice

M+F

IP RVV injection

Aza

8–17

2,5 mg/kg

Day 1,2 and 3

IP

Decreased biliary arthresia and increased survival

 Systemic Lupus Erythematodes (SLE)

 Yoshida, Izni, 1990, European journal of immunology

Mice

F

MRL-lpr mice

Aza

9–23

50 ug

2x/week from 6–21 weeks

IP

Increased survival and clinical outcome

 Mizugaki, Nose, 1997, Clin Exp Immunol

Mice

Unknown

MRL-lpr mice

Aza

4–10

50 ug

2x/week from 4–20 weeks

IP

Increased survival and clinical outcome

 Li, Tsokos, 2018, JCI Insight

Mice

F

MRL-lpr mice

Aza

4–6

5 μg (targeted to CD4+ cells)

every 10 days for 60 days

Unknown

Increased survival and clinical outcome in case of targeted delivery

Vitiligo

 Sreekumar, Smyth, 1996, Clin immunol immunopathol

Chicken

Unknown

Smyth line chicken

Aza

5–16

1 or 3 mg/kg

every 3 days up to 18 weeks

IP

Prevention of vitiligo in 1 strain, no effect in the other strain

Acute Respiratory Distress Syndrome (ARDS)

 Huang, Wang, 2016, Biomedicine & Pharmacotherapy

Mice

M

IP injection of LPS

Aza and DAC

8

1 mg/kg

1 h before LPS

IP

Alleviated lung injury

 Cui, Shang, 2019, Laboratory Investigation

Mice

M

Inhalation of LPS

Aza

6–8

1 mg/kg

1 h after LPS

IP

Alleviated lung injury

 Singer, D'alessio, 2014, Am Journal of Respiratory Cell and Molecular Biology

Mice

M

Inhalation of LPS

DAC

5–8

1 mg/kg

daily, starting 24 h after LPS

IP

Alleviated lung injury

 Thangavel, Rajasingh, 2014, Am Journal of Pathology

Mice

M

IP injection of LPS

Aza

3–5

4,4 μmol/L/kg

1 h after LPS

IP

Aza alone did not increase survival

 Thangavel, Rajasingh, 2015, Journal of Cell Science

Mice

M

IP injection of LPS

Aza

5

1 mg/kg

1 h after LPS

IP

Aza alone did not increase survival

Asthma

 Wu, Kuo, 2013, Allergy and Immunology

Mice

F

Injection and inhalation of ovalbumin

Aza

4–11

10,50,100 μg/dose

Every 3 days before OVA challenge

IP

Decreased airway hypersensitivity

 Brand, Renz, 2012, Journal of Allergy and Clinical Immunology

Mice

F

Injection and inhalation of ovalbumin

DAC

4–6

0,2 mg/kg

Every 2 days before OVA challenge

IP

Decreased airway hypersensitivity

Rheumatoid Arthritis (RA)

 Kröger, Ehrlich, 1999, General Pharmacology

Rats

M

Injection of adjuvant in the paw

Aza

3

25 mg/kg

Day 3, 5, 7, 11, 15

IP

Aza partly seemed to decrease RA

 Tóth, Rauch, 2019, Arthritis & Rheumatology

Mice

F

IP injection with proteoglycans

Aza

3–12

2 mg/kg

Every 2 days for 2 or 4 weeks

IP

Decreased RA

Multiple Sclerosis (MS)

 Chan, Wu, 2014, Molecular medicine

Mice

F

Injection of mog and heat-killed m. Tuberculosis

Aza

3–5

0,15 mg/kg/

Daily from Day-5 untill Day 10

IP

Protects against EAE

 Wang X, Tao, 2017, Oncotarget ^

Mice

M

Injection of mog and heat-killed m. Tuberculosis

DAC

5

0,25 mg/kg

Daily from Day 3 or Day 10

IP

Protects against EAE, both prevention and treatment protocol

 Mangano, Nicoletti, 2014, Journal of Cellular Physiology

Mice

M+F

Injection of mog or plp and heat-killed m. Tuberculosis

DAC

5–12

0,1 mg/kg

Daily from Day 0, Day 7 or from clinical onset

IP

Protects against EAE, both prevention and treatment protocol

Guillain Barré Syndrome (GBS)

 Fagone, Nicoletti, 2018, Journal of Neuroimmunology

Mice + Rats

M

Injection of p0 peptide and M. Tubercolosis

DAC

Unknown

0,1 mg/kg

Daily from Day 5 or from clinical onset for 21 days

IP

Decreased EAN, both prevention and treatment protocol

  1. Two articles discuss different diseases and are therefore mentioned twice in the table. They are listed with * or ^
  2. M male, F female, IP intraperitoneal, IV intravenous, SC subcutaneous, GvHD graft versus host disease, LPS lipopolysaccharides, OVA ovalbumin, MOG myelin oligodendrocyte glycoprotein, PLP proteolipid protein, EAE experimental autoimmune encephalomyelitis, EAN experimental autoimmune neuritis