Skip to main content

Table 5 Effect of checkpoint inhibitor treatment on serum and tissue cytokines, immune cell populations, and apoptosis

From: Checkpoint inhibitor therapy in preclinical sepsis models: a systematic review and meta-analysis

Author, year

Exp ID

Checkpoint molecule target

Infection organism

Infection site

Summary of the effect of checkpoint inhibitor treatment compared to control treatment

Serum cytokines

Other cytokines

Cell populations

Apoptosis

Seo, 2008

1

PD-L1

L. mono

IV

NR

Heat-killed LM-stim splenocyte TNFα, IL-12p40 and NO production and NK cell IFNγ production decreased on D+3^

Spleen LM-specific CD8s and IFNγ+ CD8s decreased on D+7 and +25^

Frequency of annexin V+ CD8s unchanged at 6 or 24 h

Brahmamdam, 2010

1

PD-1

CLP

IP

IL-6, IL-10, TNFα, IFNγ not different on D+1ns

CD3/CD28 stim splenocyte IL-6 production increased on D+2^ but IL-10, TNFα, and IFNγ not differentns

Total splenocytes, CD4, CD8, B cells, NK cells, and DCs increased on D+2^^

Splenic CD3 apoptosis decreased on D+2^^

Zhang, 2010*

1

PD-L1

CLP

IP

NR

NR

NR

NR

2

PD-L1

CLP

IP

TNFα and IL-6 increased, IL-10 decreased on D+1^

NR

Total cell numbers, CD3, and CD19 cell numbers increased on D+1 in blood, spleen, and thymus^

Splenic and thymus lymphocyte apoptosis decreased on D+1^

Inoue, 2011**

1

CTLA-4

CLP

IP

TNFα, IL-6, IL-10, IFNγ not different on D+2ns

CD3/CD28 stim splenocyte IL-6, IL-10, TNFα, IFNγ production not different on D+2ns

Total splenocyte, CD4, and CD8 numbers unchanged at D+7ns. Naïve, effector memory and central memory CD4 and CD8 unchanged at D+7ns

Splenic CD4 and CD8 apoptosis decreased on D+2^

2

CTLA-4

CLP

IP

NR

NR

NR

NR

3

CTLA-4

CLP

IP

NR

NR

NR

NR

4

CTLA-4

CLP (C.a. D+4)##

IP and IV

NR

NR

NR

NR

Kobayashi, 2013

1

BTLA

LPS

IV

NR

NR

NR

NR

Chang, 2013

1

PD-1

CLP (C.a. D+3)##

IP and IV

NR

CD3/CD28 stim splenocyte IFNγ production increased on D+9^

Macrophage and DC MHCII expression increased at D+9^

NR

2

PD-L1

CLP (C.a. D+3)##

IP and IV

NR

CD3/CD28 stim splenocyte IFNγ production not different on D+9ns IFNγ producing CD4 and CD8 increased at D+9^

Macrophage and DC MHCII expression increased at D+9^

NR

3

CTLA-4

CLP (C.a. D+3)##

IP and IV

NR

NR

NR

NR

Shindo, 2015

1

PD-1

CLP (C.a. D+3) ##

IP and IV

NR

Splenic NK, CD4, and CD8 intracellular IFNγ increased, cultured splenocyte IFNγ supernatant not different on D+9

CD28 expression on LN CD4 increased on D+9^; CD28 on splenic CD4 and CD8 not differentns; splenic and LN macrophage and DC MHCII not different on D+9

NR

Cheng, 2016

1

BTLA

CLP

IP

MIP-2 increased on D+1^ but TNFα, IL-1β, IL-6, IL-10, IL-12, KC, MCP-1 not differentns

Peritoneal lavage TNFα, IL-10, IL-12, KC, MIP-2, MCP-1 and peritoneal macrophage LPS-stim TNFα and MIP-2 increased on D+1^; IL-1β, IL-6 not different in peritoneal lavage on D+1

Total peritoneal leukocyte and F4/80, CD11c+ and Gr1+ cells increased on D+1^

Peritoneal total cell and macrophage apoptosis not different on D+1ns

Shindo, 2017

1

PD-1, PD-L1

CLP (C.a. D+3)##

IP and IV

NR

NR

NR

NR

Deng, 2018#

1

PD-L1

CLP

IP

NR

NR

NR

Splenic CD4 and CD8 apoptosis decreased on D+2 and D+3^

2

PD-L1

CLP

IP

NR

NR

NR

Splenic CD4 and CD8 apoptosis decreased on D+2 and D+3^

Patil, 2018

1

PD-L1

P. aer

ID

IL-6, IL-10, MIP-2, KC, IL-17 decreased on D+2^

Spleen and LN CD8 IFNγ production increased, LN CD4 IFNγ production decreased on D+2^ but spleen CD4 IFNγ production not differentns

Spleen and LN CD4 and CD8 cell counts increased on D+2^. LN B cell numbers increased at D+2^, not different in spleen. CD28 expression on LN CD4+ and CD8+ increased at D+2^

NR

2

PD-L1

S. aur

IV

NR

NR

NR

NR

  1. Exp ID number assigned the experiment(s) providing survival data in each study, C.a. Candida albicans, L. mono Listeria monocytogenes, S. aur Staphylococcus aureus, P. aer Pseudomonas aeruginosa, DC dendritic cell, LN lymph node, PD-1 programmed cell death 1, PD-L1 programmed death ligand-1, CTLA-4 cytotoxic T lymphocyte associated protein-4, BTLA B and T lymphocyte attenuator, CLP cecal ligation and puncture, ID intradermal, IV intravenous, IP intraperitoneal, D day, NR not reported, stim stimulated
  2. ^p < 0.05; ^^p ≤ 0.01; nsp = ns
  3. *Exp 1 treatment administered at D−1 and exp 2 treatment administered at D0
  4. **Exp 1 administered 50 μg and exp 2 administered 200 μg anti-CTLA-4 in CD-1 mice, exp 3 administered 50 μg anti-CTLA-4 in C57BL6 mice
  5. #Exp 1 performed in C57BL6J mice and exp 2 performed in Bmal1Mye-/- mice
  6. ##Intravenous Candida challenge 4 days following CLP