Re: 패혈증의 면역반응패턴(면역과잉--＞ 면역마비) PICS 중환자 단백질 분해 이유!!

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Re: 한의학의 역사를 바꿀 전침(교감-부교감신경 항염증 자극)

배경 및 임상적 중요성

패혈증은

감염에 대한 숙주 반응의 조절 이상으로 발생하는 생명을 위협하는 장기 기능 장애 증후군으로,

전 세계적으로 연간 4,890만 명 발병·1,100만 명 사망(WHO 추정).

중국 ICU 환자의 약 20%가 패혈증이며 90일 사망률 35.5%에 달함.

핵심 병태생리:

초기 과도한 염증(hyperinflammation)

→ 지속적 면역억제(immunosuppression)

→ 장기부전(MODS) 및 2차 감염 증가

→ 사망.

전통적 “하나의 크기 모두에게 맞춤” 접근(예: 항염증 단일 표적 치료)은 대부분 실패

→ 환자 간 면역 상태의 이질성(heterogeneity)과 동적 변화(dynamic immunodynamics)를

    반영한 정밀 치료(precision medicine)가 필요.

주요 내용 구조 (Fig. 1–3 기반)

1. 패혈증 면역 반응의 4가지 임상 경로 (Fig. 1)
   • 초기 다발성 장기 부전(MOF)으로 조기 사망
   • 빠른 회복
   • 후기 사망 (면역 마비 후 2차 감염 등)
   • 장기 후유증 (PICS: persistent inflammation, immunosuppression, catabolism syndrome) → SIRS → CARS → MOF → NETosis, MDSC 증가 등 복합 과정.

Activation of both proinflammatory and anti‐inflammatory immune responses occurs promptly after sepsis onset. The host response to severe sepsis can have four different clinical trajectories: (1) early MOF leading to death, (2) rapid recovery, (3) late deaths, or (4) late sequelae or long-term deaths.

SIRS : systemic inflammatory response syndrome;

CARS : compensatory anti-inflammatory response syndrome,

MOF : multi-organ failure,

NETs : Neutrophil extracellular traps,

MDSCs : Myeloid-derived suppressor cells,

ICU : intensive care unit,

PICS : persistent inflammation, immunosuppression, and catabolism syndrome.

시간축별 주요 과정 (Hours → Days/Weeks → Months/Years)

1. 초기 (몇 시간 ~ 초기 며칠) — Hyper-inflammatory phase
   • 병원체(PAMPs 등) → 강한 SIRS (전신 염증 반응 증후군) 발생
   • 사이토카인 폭풍, 응고/보체 활성화, NETs 등 → 과도하면 MOF (다발성 장기부전) → 조기 사망 (Early deaths)
2. 중기 (며칠 ~ 몇 주) — 양면적 반응
   • SIRS와 동시에/이어 CARS (보상성 항염증 반응 증후군) 발생
     • 면역 억제, 세포 사멸 증가, Treg/MDSC 확장 등
   • 결과 두 갈래:
     • 빠른 회복 → 면역 항상성 회복 (좋은 경과)
     • 지속 → PICS (Persistent Inflammation, Immunosuppression, Catabolism Syndrome)로 진행
3. 후기 (몇 주 ~ 몇 달/년) — Hypo-inflammatory & 만성 단계
   • PICS 특징: 지속 염증 + 면역억제 + 단백질 분해(근육 소모, 캐시엑시아)
   • 장기 입원(≥14일), 재발 감염, 지속 장기부전, 상처 치유 지연 → 장기 사망 또는 만성 중환자 상태 (Late / Long-term deaths)

면역 불균형의 세포·분자 기전 (Fig. 2)

• 선천 면역:
  • TLR4/NF-κB/MAPK 경로 과활성화 → 사이토카인 폭풍 (TNF-α, IL-1, IL-6 등)
  • 대식세포 아폽토시스, NETosis 과도, NK 세포 기능 저하, 수지상세포(DC) 마비
• 적응 면역:
  • T세포 (CD4/CD8) 대량 아폽토시스
  • 억제 수용체 과발현 (PD-1, CTLA-4, TIM-3, LAG-3, TIGIT, VISTA) → T세포 소진(exhaustion)
  • Th1/Th2/Th17/Treg 불균형 (Th2/Th17 우세, Treg 증가)
  • 단핵구 비활성화 (HLA-DR ↓) → 결과: 병원체 제거 실패 + 지속적 면역억제.
  • A. 선천 면역 세포 (Innate immune cells)
    • 세포 종류: 대식세포/단핵구(Macrophages/Monocytes), 호중구(Neutrophils), NK 세포(Natural killer cells), 수지상세포(Dendritic cells)
    • 대식세포: M1-like 극성화 → 염증 매개체 ↑
    • 호중구: NETs 형성 ↑, pro-inflammatory mediators ↑
    • NK 세포: IFN-γ ↑, M1 macrophages 유도 ↑
    • 수지상세포: T 세포 유도 ↑, pro-inflammatory mediators ↑ (전체적으로 적응 면역도 활성화시키는 방향)
    • 공통: 순환 수 ↓, pro-inflammatory cytokine 분비 ↓, apoptosis ↑, PD-1 ↑
    • 대식세포/단핵구: HLA-DR ↓, anti-inflammatory cytokine (IL-10 등) ↑, M2 phenotype 전환, pinocytosis/phagocytosis 장애
    • 호중구: chemotaxis/oxidative burst ↓, immature neutrophil ↑, IL-10 ↑
    • NK 세포: cytotoxic 기능 ↓, apoptosis ↑
    • 수지상세포: HLA-DR ↓, CD86 ↓, anti-inflammatory cytokine ↑, apoptosis ↑ → 면역 마비(immunoparalysis) 상태 → 2차 감염 취약
    B. 적응 면역 세포 (Adaptive immune cells)
    • 세포 종류: CD4⁺ T 세포, CD8⁺ T 세포, Treg 세포, B 세포
    • CD4⁺ T: 다양한 Th lineage (Th1/Th17 등) 극성화 → pro-inflammatory mediator ↑
    • CD8⁺ T: cytotoxic 효과 ↑
    • Treg: 자가 관용 유지, M2 macrophage 유도
    • B 세포: 항체 생산 ↑, immune regulation
    • 공통: apoptosis ↑, proliferation ↓, pro-inflammatory cytokine ↓
    • CD4⁺ T: TCR diversity ↓, Th2 polarization ↑, exhaustion, PD-1 ↑
    • CD8⁺ T: cytotoxic 기능 ↓, TCR diversity ↓, PD-1 ↑, exhaustion
    • Treg: apoptosis ↓ (상대적 증가), anti-inflammatory cytokine ↑, Foxp3 ↑, CTLA-4 ↑ → 억제 강화
    • B 세포: 항원 특이적 항체 생산 ↓, circulating number ↓, HLA-DR ↓, anti-inflammatory cytokine ↑, exhaustion

현재 치료의 한계와 실패 사례

• 항염증 약물: 항-TNF-α (CytoFab), IL-1 수용체 길항제(anakinra), TLR4 길항제(eritoran), 고용량 스테로이드 등 → 대부분 대규모 RCT에서 사망률 감소 실패.
• 이유: 단일 표적 → 복합적·동적 면역 네트워크 무시, 과도 억제 시 면역 마비 악화 가능.

잠재적 면역치료 전략 (Fig. 3)

• 과염증 억제: 항-IL-1, 항-TNF-α, TLR4 차단, 글루코코르티코이드 (특정 subgroup에서 효과), ulinastatin, Xuebijing (중약), MSCs
• 면역 강화: GM-CSF, IFN-γ, IL-7, G-CSF → HLA-DR 회복, T세포 기능 개선
• 면역 체크포인트 억제: anti-PD-1/PD-L1, anti-CTLA-4 → 동물 모델에서 생존율 향상
• 기타: IL-33, TIM-3 조절 등 신규 표적 → subgroup 분석(예: mALS, hepatobiliary dysfunction) 또는 바이오마커 기반(HLA-DR, ferritin, suPAR, gene expression‎ endotypes)에서 일부 성공.
  • Polymyxin B → LPS (내독소) 중화 → TLR4 경로 차단
  • TLR4 antagonist → TLR4 수용체 직접 차단
  • Ulinastatin (울리나스타틴) → 프로염증 매개체 (IL-1, TNF-α, IL-6 등) 억제
  • Specific antibodies → 염증 매개체 직접 중화 (anti-TNF-α, anti-IL-1 등)
  • Glucocorticoids (스테로이드) → 광범위 항염증
  • Clarithromycin (클라리스로마이신) → 항생제 외에 면역 조절 효과 (cytokine 억제, 균 제거 촉진) → 최근 연구에서 sepsis 환자 hyperinflammation 완화 효과 입증 (예: cytokine storm 감소, 면역 균형 회복)
  • G-CSF / GM-CSF → 골수에서 호중구/단핵구 동원(mobilization) → monocyte 기능 회복, HLA-DR ↑
  • Thymosin alpha 1 (타이모신 α1) → T 세포 성숙/활성화 촉진 → severe sepsis에서 28일 사망률 감소 (meta-analysis 지원)
  • IFN-γ (인터페론 감마) → monocyte 활성화, HLA-DR ↑, DC 기능 회복 → 면역 마비 역전
  • IL-7 → T 세포 apoptosis 차단 + 활성화 → lymphopenia 개선, 최근 임상시험에서 CD4/CD8 T 세포 수 3~4배 증가 (cytokine storm 없이)
  • IL-15 → NK/T 세포 활성화 + apoptosis 차단
  • IL-33 → 광범위 면역 활성화
  • Immunoglobulin (면역글로불린) → 보체 활성화, LPS 중화, phagocytosis 촉진
  • Mesenchymal stem cell (중간엽 줄기세포) → 항염증 + 재생 효과
  • Immune checkpoint inhibitors (PD-1/PD-L1, CTLA-4, LAG-3 등 blocker) → T 세포 exhaustion 역전 → PICS 면역 억제 타깃 (암 면역요법에서 빌려온 전략, sepsis 연구 활발)

주요 결론 및 열린 질문

• 패혈증은 단일 치료법으로는 해결 불가능 → 면역 상태에 따른 개인화 치료(immune stratification)가 핵심.
• 조기 경고 시스템 + 실시간 바이오마커 모니터링 + AI/멀티오믹스 기반 endotype 분류 필요.
• 열린 질문:
  1. 효과적인 바이오마커·면역 체크포인트 조기 발견 방법?
  2. 다양한 면역 세포 기능 장애 기전 규명?
  3. 다기관 설정에서의 전향적·범용적 정밀 치료 연구?

1. nature  
2. cell death discovery  
3. review articles  
4. article

Immune dysregulation in sepsis: experiences, lessons and perspectives

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• Review Article
• Open access
• Published: 19 December 2023

Immune dysregulation in sepsis: experiences, lessons and perspectives

• Min Cao, 
• Guozheng Wang & 
• Jianfeng Xie 

Cell Death Discovery volume 9, Article number: 465 (2023) Cite this article

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Abstract

Sepsis is a life-threatening organ dysfunction syndrome caused by dysregulated host responses to infection. Not only does sepsis pose a serious hazard to human health, but it also imposes a substantial economic burden on the healthcare system. The cornerstones of current treatment for sepsis remain source control, fluid resuscitation, and rapid administration of antibiotics, etc. To date, no drugs have been approved for treating sepsis, and most clinical trials of potential therapies have failed to reduce mortality. The immune response caused by the pathogen is complex, resulting in a dysregulated innate and adaptive immune response that, if not promptly controlled, can lead to excessive inflammation, immunosuppression, and failure to re-establish immune homeostasis. The impaired immune response in patients with sepsis and the potential immunotherapy to modulate the immune response causing excessive inflammation or enhancing immunity suggest the importance of demonstrating individualized therapy. Here, we review the immune dysfunction caused by sepsis, where immune cell production, effector cell function, and survival are directly affected during sepsis. In addition, we discuss potential immunotherapy in septic patients and highlight the need for precise treatment according to clinical and immune stratification.

패혈증(sepsis)은 감염에 대한 숙주 반응의 조절 이상으로 인해 발생하는 생명을 위협하는 장기 기능 장애 증후군이다. 패혈증은 인간 건강에 심각한 위험을 초래할 뿐만 아니라 의료 시스템에 상당한 경제적 부담을 가중시킨다. 현재 패혈증 치료의 기본 원칙은 감염원 제거(source control), 수액 소생술(fluid resuscitation), 신속한 항생제 투여 등으로 유지되고 있다. 지금까지 패혈증 치료를 위해 승인된 약물은 없으며, 잠재적 치료제들의 대부분의 임상 시험은 사망률 감소에 실패하였다.

병원체에 의한 면역 반응은 매우 복잡하여 선천 면역과 적응 면역 모두가 조절 이상(dysregulated) 상태에 빠지게 되며, 이를 적시에 통제하지 못하면 과도한 염증(excessive inflammation), 면역억제(immunosuppression), 그리고 면역 항상성(immune homeostasis)의 재확립 실패로 이어진다. 패혈증 환자에서 나타나는 면역 반응 장애와, 과도한 염증을 조절하거나 면역력을 강화하는 잠재적 면역요법(immunotherapy)의 가능성은 개별화된 치료(individualized therapy)의 중요성을 시사한다.

본 논문에서는 패혈증으로 인해 발생하는 면역 기능 장애를 검토한다. 여기서 면역 세포의 생성(immune cell production), 효과 세포의 기능(effector cell function), 생존(survival)이 패혈증 동안 직접적으로 영향을 받는다. 또한 패혈증 환자에서 가능한 면역요법을 논의하고, 임상적·면역학적 층화(clinical and immune stratification)에 따른 정밀 치료(precise treatment)의 필요성을 강조한다.

Article 24 September 2025

Facts

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Introduction

Sepsis is a life-threatening, complex clinical and biochemical syndrome characterized by acute organ dysfunction that develops due to the body’s dysfunctional response to microbial invasion [1]. Sepsis remains a significant cause of health loss worldwide, with an estimated 48.9 million incident cases of sepsis and 11 million sepsis-related deaths [2]. Our previous cross-sectional study revealed that sepsis impacted one-fifth of ICU-admitted patients and has a 90-day mortality rate of 35.5%, indicating a substantial burden of sepsis on the Chinese mainland [3]. The pathophysiology of sepsis is complex when the pathogen evades the host’s defense mechanisms and continuously stimulates and damages host cells so that many of the immune mechanisms initially activated to provide protection have become deleterious due to the inability to restore homeostasis, leading to persistent hyperinflammation and immunosuppression [4]. From the 1970s until the early 2000s, it was widely recognized that the high mortality rate in sepsis was caused by multiple organ failure due to immune damage resulting from an excessive inflammatory response. However, all anti-inflammatory therapy strategies were failed in clinical trials. In recent years, a substantial body of research has shown that sepsis is characterized by concurrent dysregulation of the innate immune system and suppression of the adaptive immune system. This simultaneous imbalance and persistence of inflammatory and anti-inflammatory responses ultimately culminate in recurrent and persistent infections, organ dysfunction, and ultimately, fatality for the patient (Fig. 1). Numerous individuals afflicted with sepsis may experience a comparatively concise phase of hyperinflammation, nonetheless are susceptible to developing immunocompromised states due to extended hospitalization and recuperation. Indeed, a significant proportion of individuals with sepsis die from secondary or opportunistic infections while in a condition of immunosuppression. Hence, it is imperative to ascertain the immune status of individuals with sepsis, elucidate the clinical and immunological categorization of patients, and effectively regulate the exaggerated inflammatory response and immunosuppressive condition of the septic patient’s body, all of which are crucial in the management of sepsis. Here, we review the key factors of immune dysregulation in sepsis and potential precision immunotherapies.

서론

패혈증(sepsis)은

미생물 침입에 대한 신체의 비정상적인 반응으로 인해 발생하는 급성 장기 기능 장애를 특징으로 하는

생명을 위협하는 복잡한 임상 및 생화학적 증후군이다[1].

패혈증은

전 세계적으로 건강 손실의 주요 원인으로 남아 있으며,

추정치로 연간 4,890만 건의 패혈증 발병 사례와

1,100만 건의 패혈증 관련 사망이 발생한다[2].

우리의 이전 단면 연구에 따르면,

패혈증은 중환자실(ICU)에 입원한 환자의 5분의 1에 영향을 미쳤으며

90일 사망률은 35.5%로, 중국 본토에서 패혈증이 상당한 부담을 주고 있음을 보여준다[3].

패혈증의 병태생리는

병원체가 숙주의 방어 기전을 회피하고 지속적으로

숙주 세포를 자극·손상시킬 때 매우 복잡해지며,

처음에는 보호를 위해 활성화된 많은 면역 기전들이 항상성을 회복하지 못해 해로워지게 되어

지속적인 과염증(hyperinflammation)과 면역억제(immunosuppression)로 이어진다[4].

1970년대부터 2000년대 초반까지는

패혈증의 높은 사망률이 과도한 염증 반응으로 인한 면역 손상과

그로 인한 다발성 장기 부전(multiple organ failure) 때문이라고 널리 인식되었다.

그러나

모든 항염증 치료 전략은 임상 시험에서 실패했다.

최근 수년간 상당한 연구 결과에 따르면,

패혈증은 선천 면역계의 dysregulation과 적응 면역계의 억제가 동시에 발생하는 특징을 보이며,

이러한 염증과 항염증 반응의 불균형 및 지속이

결국 재발성·지속성 감염, 장기 기능 장애,

그리고 환자의 사망으로 이어진다(그림 1).

패혈증에 걸린 많은 환자들은

비교적 짧은 과염증 단계를 경험할 수 있으나,

장기 입원과 회복 과정에서 면역저하 상태에 취약해진다.

실제로 패혈증 환자의 상당수는

면역억제 상태에서 2차 감염 또는 기회감염으로 사망한다.

따라서

패혈증 환자의 면역 상태를 파악하고,

환자를 임상적·면역학적으로 분류하며,

과도한 염증 반응과 면역억제 상태를 효과적으로 조절하는 것이 패혈증 관리에서 매우 중요하다.

여기서는

패혈증에서의 면역 dysregulation의 주요 요인과 잠재적인 정밀 면역요법(precision immunotherapies)을 검토한다.

Fig. 1: Host immune response in sepsis.

Activation of both proinflammatory and anti‐inflammatory immune responses occurs promptly after sepsis onset. The host response to severe sepsis can have four different clinical trajectories: (1) early MOF leading to death, (2) rapid recovery, (3) late deaths, or (4) late sequelae or long-term deaths.

SIRS, systemic inflammatory response syndrome; CARS compensatory anti‐inflammatory response syndrome, MOF multi-organ failure, NETs Neutrophil extracellular traps, MDSCs Myeloid-derived suppressor cells, ICU intensive care unit, PICS persistent inflammation, immunosuppression, and catabolism syndrome.

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Immune dysregulation in sepsis

Innate and adaptive immune cells activated by pathogen invasion relocate locally to tissues to prevent microbial multiplication and spread, and immunological homeostasis is attained when inflammation is controlled. During the onset of sepsis, pro-inflammatory and anti-inflammatory processes are activated simultaneously. Innate and adaptive immune cells triggered by both pathogens and DAMPs are in a state of hyperinflammation, and cytokine storms produced by immune cells block infections to some extent but also contribute to severe tissue damage. Pathogens can spread throughout the body through damaged blood vessels, causing an intense inflammatory response, leading to systemic immune dysregulation and injury. Depletion of innate and adaptive immune cells through apoptosis can lead to immunosuppression. Multiple factors influence the immune response in sepsis, including co-morbidities (e.g., malignancy, diabetes, heart disease), the microbial inoculum quantity, and the pathogen’s virulence. The principal pathogens causing sepsis include bacteria, fungi, and viruses. Superantigens of Gram-positive bacteria can cause significant direct harm to host cells. Lipopolysaccharides, the surface toxins of Gram-negative bacteria, can stimulate specific toll-like receptors, leading to a devastating immune response. Although the clinical appearance of viral sepsis is similar to that of bacterial sepsis, the immunological response is different. Macrophages boost the production of type I and type II interferons after exposure to the virus, and further activated neutrophils and lymphocytes play a critical role against the virus. Unlike other pathogens, fungal infections are usually connected with a situation of immunosuppression, and it is only after an immunological imbalance that the fungus invades deeper tissues, leading to sepsis. Fungal sepsis, hence, has a higher mortality rate compared to viral and bacterial sepsis. The progression of sepsis follows a certain pattern of immunodynamic change, with patients having distinct immune statuses at different times and stages, and the same immune cells presenting varied patterns of immune status. Innate and adaptive immune responses are considerably altered during the development of sepsis, which may impair the host’s ability to destroy invading pathogens, further leading to the recurrence of latent infections and susceptibility to secondary infections (Fig. 2).

(패혈증에서의 면역 dysregulation)

병원체 침입에 의해 활성화된 선천 및 적응 면역 세포들은

미생물의 증식과 확산을 막기 위해 국소적으로 조직으로 이동하며,

염증이 조절되면 면역 항상성(immunological homeostasis)이 회복된다.

패혈증 발병 시에는

프로염증(pro-inflammatory) 및 항염증(anti-inflammatory) 과정이 동시에 활성화된다.

병원체와 DAMPs(damage-associated molecular patterns)에 의해 유발된

선천 및 적응 면역 세포들은 과염증(hyperinflammation) 상태에 빠지며,

면역 세포들이 생산하는 사이토카인 폭풍(cytokine storm)은

감염을 어느 정도 차단하지만 동시에 심각한 조직 손상을 유발한다.

병원체는

손상된 혈관을 통해 전신으로 퍼질 수 있으며,

이는 강렬한 염증 반응을 일으켜 전신 면역 dysregulation과 손상을 초래한다.

선천 및 적응 면역 세포의 아포토시스(apoptosis)를 통한 고갈은

면역억제(immunosuppression)로 이어진다.

패혈증에서의 면역 반응에는 여러 요인이 영향을 미친다.

여기에는

동반 질환(예: 악성종양, 당뇨병, 심장 질환),

미생물 접종량(microbial inoculum quantity),

병원체의 독력(virulence) 등이 포함된다.

패혈증의 주요 병원체는

세균, 진균, 바이러스이다.

• 그램 양성균의 슈퍼항원(superantigens)은 숙주 세포에 직접적인 심각한 손상을 유발할 수 있다.
• 그램 음성균의 표면 독소인 리포다당류(lipopolysaccharides, LPS)는 특정 톨-유사 수용체(toll-like receptors)를 자극하여 파괴적인 면역 반응을 일으킨다.
• 바이러스 패혈증은 임상적으로 세균 패혈증과 유사하지만 면역 반응은 다르다. 바이러스 노출 후 대식세포(macrophages)는 1형 및 2형 인터페론(type I and II interferons) 생산을 증가시키며, 추가로 활성화된 호중구(neutrophils)와 림프구(lymphocytes)가 바이러스에 대항하는 데 중요한 역할을 한다.
• 진균 감염은 대개 면역억제 상태와 관련이 있으며, 면역 불균형이 발생한 후에야 진균이 깊은 조직으로 침투하여 패혈증을 일으킨다. 따라서 진균 패혈증은 바이러스 및 세균 패혈증에 비해 사망률이 더 높다.

패혈증의 진행은

일정한 면역동태 변화(immunodynamic change) 패턴을 따르며,

환자들은 시간과 단계에 따라 뚜렷하게 다른 면역 상태를 보인다.

동일한 면역 세포라도

시기와 단계에 따라 다양한 면역 상태 패턴을 나타낸다.

패혈증 발병 과정에서 선천 및 적응 면역 반응은 상당히 변화하며,

이는 숙주가 침입 병원체를 제거하는 능력을 저하시켜

잠복 감염의 재발과 2차 감염에 대한 취약성을 더욱 증가시킨다(그림 2).

Fig. 2: Sepsis-induced immune dysregulation.

A Innate immune dysfunction in sepsis. B Adaptive immune dysfunction in sepsis. When septic insults happen, both the innate and adaptive immune responses are drastically changed. Shortly after detection of an infectious agent, the innate immune cells attempt to clear the overwhelming infection as quickly as possible, followed by activation of the adaptive immune system through activation of the Th cells and cytotoxic T cells. Under normal conditions, after the resolution of the infection, the patient’s body will return to homeostasis. In inflammatory responses due to severe infections, immune cells undergo various phenotypic changes as the immune system fails to resolve inflammation appropriately. Immune cell production, effector cell function, and survival are directly affected, resulting in ubiquitous immunosuppression.

HLA-DR human leukocyte antigen-antigen D related,

PD-1 programmed cell death protein 1,

IL interleukin,

TCR T-cell receptor.

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During early sepsis, macrophages’ toll-like receptor 4 (TLR4) recognizes LPS, activating the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways to release proinflammatory cytokines and clear pathogenic microorganisms [5]. Meanwhile, massive apoptosis of macrophages and secretion of large amounts of anti-inflammatory mediators by M2-like macrophages make it difficult for the host to respond effectively to the pathogen. Excessive neutrophil activation and neutrophil extracellular traps (NETs) release may induce a shift in endothelial cells toward a proinflammatory and procoagulant phenotype and macrophage polarization toward the M1 phenotype [6, 7]. However, pro-inflammatory cytokines can upregulate guanosine cerebrospinal fluid levels, which can lead to an excessive release of circulating immature neutrophils [8]. NK cells activation is dysregulated and secretes large amounts of cytokines, contributing to a positive feedback loop and amplifying the pro-inflammatory cytokine storm [9]. However, the number of NK cells, cytokine production, and cytotoxic proteins from NK cells are decreased during the immunosuppressive stage of sepsis. Sepsis also can lead to apoptosis of dendritic cells(DCs) cells, block their maturation process and induce paralysis to reduce the number of DCs [10]. In addition, the levels of surface molecules associated with the function of DCs are changed, leading to immune tolerance.

Numbers of CD4 T cells decrease after the onset of sepsis, and absolute CD4 T-cell numbers return to pre-septic levels after a month in most patients, but failure to restore sufficient numbers of immunocompetent CD4 T cells is associated with a poor prognosis [11, 12]. Impaired CD4 T cell function after sepsis, characterized by decreased cytokine secretion and increased expression‎ of inhibitory receptors, restricts the assistance provided to other immune cells [13]. Sepsis also disrupts the expression‎ and function of CD4T cell subsets (Th1, Th2, Th17 and Treg subsets). Our previous study showed that Th2/Th1 values were significantly upregulated in previously immunocompetent patients at the onset of community-acquired severe sepsis, and their sustained dynamic increase was associated with ICU-acquired infection and 28-day mortality [14]. The Th17/Treg balance is regarded as a key factor in the homeostasis of the internal immune environment, and imbalance has been shown to be associated with the aggravation of illness in patients with sepsis [15]. Additionally, the composition and phenotype of the circulating CD8 T cell pool are altered after sepsis, inducing a rapid loss of naïve CD8 T cells and memory CD8 T cells leading to transient lymphocytopenia with early signs of immune paralysis [16]. B-cell number, phenotype, and effector functions are also significantly altered in sepsis patients and are inconsistent across populations [17]. Our current understanding of immune cells in the development of sepsis remains limited, but scientific advances continue to fill critical knowledge gaps and are also gradually identifying new potential therapeutic targets.

패혈증 초기 단계에서의 면역 세포 변화

패혈증 초기에는

대식세포(macrophages)의 톨-유사 수용체 4(TLR4)가 LPS(lipopolysaccharide)를 인식하여

nuclear factor-κB(NF-κB)와 mitogen-activated protein kinase(MAPK) 경로를 활성화시키며,

프로염증성 사이토카인(proinflammatory cytokines)을 방출하고

병원성 미생물을 제거한다[5].

동시에

대식세포의 대량 아포토시스(apoptosis)와

M2-like 대식세포에 의한 다량의 항염증 매개체(anti-inflammatory mediators) 분비로 인해

숙주가 병원체에 효과적으로 대응하기 어려워진다.

과도한 호중구(neutrophil) 활성화와 호중구 세포외 덫(neutrophil extracellular traps, NETs) 방출은

내피세포(endothelial cells)를 프로염증성(proinflammatory) 및 프로응고성(procoagulant) 표현형으로 전환시키고,

대식세포를 M1 표현형으로 극성화(polarization)시킬 수 있다[6, 7].

그러나

프로염증성 사이토카인은

guanosine cerebrospinal fluid(구아노신 뇌척수액) 수치를 상향 조절하여

순환 중 미성숙 호중구(immature neutrophils)의 과도한 방출을 유발할 수 있다[8].

NK 세포(natural killer cells)의 활성화는

dysregulation되어 다량의 사이토카인을 분비하며,

이는 양성 피드백 루프(positive feedback loop)를 형성하여

프로염증성 사이토카인 폭풍(cytokine storm)을 증폭시킨다[9].

그러나

패혈증의 면역억제 단계(immunosuppressive stage)에서는

NK 세포 수, 사이토카인 생산, 그리고 세포독성 단백질(cytotoxic proteins)이 감소한다.

패혈증은

또한 수지상세포(dendritic cells, DCs)의 아포토시스를 유발하고,

DCs의 성숙 과정을 차단하며 마비(paralysis)를 유도하여

DCs 수를 감소시킨다[10].

또한

DCs 기능과 관련된 표면 분자(surface molecules) 수준이 변화하여

면역 관용(immune tolerance)을 초래한다.

패혈증 발병 후 CD4 T 세포 수가 감소하며,

대부분의 환자에서 1개월 후 절대 CD4 T 세포 수가 패혈증 이전 수준으로 회복되지만,

충분한 면역능력 있는 CD4 T 세포 수를 회복하지 못하는 경우

예후가 불량하다[11, 12].

패혈증 후 CD4 T 세포 기능 장애는

사이토카인 분비 감소와 억제 수용체(inhibitory receptors) 발현 증가를 특징으로 하며,

다른 면역 세포에 대한 도움 제공을 제한한다[13].

패혈증은

또한 CD4 T 세포 아형(Th1, Th2, Th17, Treg)의 발현과 기능을 교란시킨다.

우리의 이전 연구에서는

이전에 면역능력이 정상이었던 환자에서 지역사회 획득 중증 패혈증(community-acquired severe sepsis) 발병 시

Th2/Th1 비율이 유의하게 상승하였으며,

이 비율의 지속적인 동적 증가가

중환자실 내원 감염(ICU-acquired infection) 및 28일 사망률과 관련이 있음을 보여주었다[14].

Th17/Treg 균형은

내부 면역 환경 항상성(homeostasis)의 핵심 요인으로 간주되며,

이 균형의 불균형은 패혈증 환자의 질병 악화와 관련이 있다[15].

또한 패혈증 후 순환 CD8 T 세포 풀의 구성과 표현형이 변화하여 naïve CD8 T 세포와 memory CD8 T 세포의 급속한 손실을 유발하며, 이는 초기 면역 마비(immune paralysis)의 징후와 함께 일시적인 림프구감소증(lymphocytopenia)을 초래한다[16]. B 세포 수, 표현형, 그리고 효과기 기능(effector functions) 역시 패혈증 환자에서 유의하게 변화하며, 인구 집단에 따라 일관되지 않는다[17].

현재 패혈증 발병 과정에서의 면역 세포에 대한 이해는 여전히 제한적이지만, 과학적 발전이 중요한 지식 공백을 메우고 있으며, 점차 새로운 잠재적 치료 표적(therapeutic targets)을 식별하고 있다.

Immunotherapy

Imbalance of the immune system in sepsis patients is one of the main causes of their poor prognosis. The pathogenesis of sepsis includes not only excessive inflammatory response, but also a number of molecular and cellular events that contribute to immunosuppression. Numerous clinical studies on immunotherapy have focused on how to modulate immune response and enhance immunity in patients with sepsis (Supplemental Table 1). Restoring immune function and immune balance can reduce harm to organ function in patients with immune imbalances, protecting the organs.The regulatory effect on the immune-response modulation is primarily concerned with the inflammatory response, i.e. the balancing and regulating effect on the inflammatory response. Immunity enhancement can further maintain the immune homeostasis of the organism through the reconstruction of immune function. Many patients with sepsis have a relatively brief phase of hyperinflammation, so the success of drugs targeting inflammation may be effective only for a very short period of time. Patients with sepsis may also become immunocompromised, so a “one-size-fits-all” treatment strategy for sepsis-induced immune imbalance is bound to fail. In general, precise regulation of the excessive inflammatory response and immunosuppressive state of the body in sepsis patients is the key to treating sepsis (Fig. 3).

Fig. 3: Potential immunotherapy for patients with sepsis-modulate the immune responses or enhance immunity.

A Modulate immune responses that provoke excessive inflammation during sepsis. B Enhance immunity during sepsis. The immune response in sepsis is a highly individualized process. Sepsis patients’ immune responses vary depending on their immunological condition at the time of infection, age, comorbidities, environmental variables, and microbiome. Precise immunotherapy can significantly improve the prognosis of sepsis. LPS lipopolysaccharide, TLR4 toll like receptor 4, IL interleukin, TNF-α tumor necrosis factor-alpha, G-CSF Granulocyte colony-stimulating factor, GM-CSF granulocyte macrophage colony stimulating factor, IFN-γ interferon-gamma, APC antigen-presenting cell.

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Modulate immune responseSpecific antibodies of inflammatory mediatorsIL-1

IL-1ra administration in late sepsis decreases hypothalamic oxidative stress and increases vasopressin production, enhancing blood pressure and animal survival [18]. Knaus et al. found that patients with sepsis treated with recombinant human (rh)IL-1ra had a significant increase in survival time [19]. However, a further retrospective analysis showed that survival was not statistically significant in all patients treated with rIL-1ra compared with the placebo group [20]. The study by Opal et al. was terminated after an interim analysis found that a 72-hour continuous intravenous infusion of anakinra(rIL-1ra) failed to reduce mortality statistically significantly [21]. A reanalysis by Shakoory et al. found that anakinra significantly improved survival in patients with sepsis complicated by hepatobiliary dysfunction and disseminated intravascular coagulation (HBD/DIC) [22]. Based on early soluble urokinase plasminogen activator receptor(suPAR), subcutaneous anakinra reduced severe respiratory failure and restored the pro/anti-inflammatory balance [23]. The PROVIDE trial defined a rapid classification of sepsis from an immunological perspective in patients with macrophage activation-like syndrome (mALS), or immune paralysis who were randomly assigned to anakinra or rhIFNγ or placebo treatment groups, with 42.9% of patients surviving after 7 days with a decrease in sequential organ failure assessment (SOFA) score [24]. In the ongoing clinical trial (NCT04990232), based on the measurement of circulating ferritin and HLA-DR expression‎, patients were classified as hyper-inflammatory or immunoparalysis and were randomly assigned to either a placebo arm or an immunotherapy arm(anakinra or rhIFN-γ) [25]. The above studies show that treatment with anakinra in personalized adjuvant immunotherapy is promising but should be confirmed with more optimized trial protocols in future studies. The above studies suggest that personalized adjuvant immunotherapy after determining a patient’s immunophenotype will hopefully benefit sepsis patients.

TNF-α

Neutralizing monoclonal anti-cachectin/TNFα monoclonal antibodies injected only one hour before a bacterial attack in baboons prevented shock, while two hours prevented essential organ dysfunction and mortality [26]. In patients with severe sepsis or septic shock, high doses of the murine anti-TNF-α antibody, CB0006, were well tolerated, with a tendency to improve survival in the subgroup with high plasma TNF-α concentrations [27]. Polyclonal ovine anti-TNF-α fragment antigen binding (Fab) fragments (CytoFab) on plasma TNF-α were effectively reducing serum and BAL TNF-α and serum IL-6 concentrations, and increasing the number of ventilator-free and ICU-free days at day 28 [28]. Reinhart et al. retrospectively stratified severe sepsis or septic shock patients based on IL-6 concentrations and showed that MAK 195 F reduced mortality in patients with baseline IL-6 concentrations above 1000 pg/mL [29]. However, the subsequent study of sepsis patients with IL-6 concentrations >1000 pg/mL who were randomly assigned to receive afeliomab or placebo was terminated early after the primary efficacy endpoint was estimated not to be met due to interim analysis [30]. More and more research is showing that immune dysregulation in sepsis cannot be attributed to a single cytokine or cell population alteration. Future clinical research may focus on stratifying sepsis patients according to specific biomarkers; however, the management of sepsis is a gradual endeavor.

IL-3

IL-3 promotes myelopoiesis and cytokine storm in cecal ligation and puncture (CLP)-induced acute sepsis, and inhibiting IL-3 activity protected mice from sepsis-induced increases in neutrophils, inflammatory monocytes, and inflammatory cytokines, reducing organ damage and improving survival [31]. Anti-IL-3 antibody treatment significantly improved survival in septic mice, possibly associated with increased Treg percentage and function [32]. IL-3 has a dual role in sepsis, stimulating innate immune responses that are detrimental in the acute phase but protective in the immunosuppressive phase by improving antiviral defense mechanisms. IL-3 also could protect viral pneumonia in sepsis by promoting the recruitment of circulating plasmacytoid DCs into the lung and T cell initiation [33]. High levels of IL-3 in the plasma of septic patients are associated with increased mortality [31].

TLR4

TLR4 deficiency or antibody blockade has been shown to be beneficial and can effectively protect animals from sepsis-induced shock and high mortality [34, 35]. NI-0101 is the first monoclonal antibody to block TLR4 signaling and prevent cytokine release in healthy volunteers after receiving LPS [36]. Patients with high APACHE scores may benefit from eritoran, a synthetic lipodisaccharide that binds to MD2-TLR4 and competitively blocks LPS to TLR4 [37]. Unfortunately, eritoran was withdrawn from further clinical testing in 2011, which failed to be efficacious in clinical trials [38]. In a randomized, double-blind, placebo-controlled trial, TAK-242 treatment did not suppress cytokine levels or reduce 28-day all-cause mortality in patients with severe sepsis [39]. Due to septic patients’ complicated and varied immunological status, TLR4 inhibitors may benefit patients early in the sepsis’ inflammatory phase or in combination with other medicines.

Glucocorticoids

The first clinical trial using glucocorticoids for sepsis demonstrated a significant mortality reduction in patients with high-dose glucocorticoids [40]. However, later studies reported that short-term administration of high-dose glucocorticoids was associated with worsening secondary infection and increased risk of death, and that low to moderate doses of glucocorticoids also did not improve survival or shock reversal in sepsis [41,42,43,44]. Combining hydrocortisone with fludrocortisone significantly reduced 90-day all-cause mortality in patients with septic shock [45]. A recent meta-analysis of metabolic resuscitation with vitamin C, glucocorticoids, vitamin B1, or a combination of these drugs did not significantly reduce long-term mortality (90 days to 1 year) in adults with sepsis or septic shock compared with placebo/usual care [46]. 25-60% of patients with sepsis experience relative adrenal insufficiency (RAI). Glucocorticoid treatment of mice with CLP-induced sepsis was found to be beneficial in RAI mice but detrimental in mice without RAI [47]. In the first phase 3 trial by Annane et al., low doses of hydrocortisone significantly reduced mortality in patients with septic shock and RAI [48]. Genome-wide profiling of peripheral blood leukocytes from septic patients defined two distinct sepsis response signatures (SRS1 and SRS2) [49, 50]. Antcliffe et al. showed that septic patients with the immunocompetent SRS2 endocrine phenotype had significantly higher mortality with corticosteroids [51]. Genome-wide expression‎ profiling using microarray technology and analytics may target a subclass of patients to benefit most from immunotherapy, providing personalized and precision medicine. Thus, further precision medicine approaches based on the RAI and SRS2 endocrine phenotype in patients with sepsis will probably benefit patients from glucocorticoids treatment, which needs further validation in clinical trials.

Other immunomodulatory drugs

Ulinastatin (UTI) is a multifunctional Kunitz-type serine protease inhibitor with anti-inflammatory and neuroprotective effects [52]. Intravenous administration of UIT inhibits inflammatory mediators and lymphocyte apoptosis levels in CLP-model mice with sepsis [53]. A retrospective study found that the use of UTI in 263 patients with severe sepsis reduced mortality by 23.5% [54]. However, in a multicenter randomized controlled study, UIT treatment reduced all-cause mortality at 28 days in a multivariate analysis, however there was no statistical difference in mortality in the intention-to-treat analysis [55]. A meta-analysis including 13 studies showed that UIT improved all-cause mortality, APACHE II scores, and inflammatory cytokine profiles in patients with sepsis or septic shock [56]. There remains an urgent need for larger randomized clinical trials to eval‎uate the impact of UTI in patients with sepsis.

Xuebijing (XBJ) injection is a Chinese herbal medicine containing extracts from five herbs, and it has been incorporated into the routine sepsis care in China since 2004. XBJ inhibited inflammation and regulated Tregs/Th17 in various animal models of sepsis [57,58,59]. Our previous multicenter, randomized, double-blind, placebo-controlled trial showed that treatment with XBJ reduced 28-day mortality in patients with sepsis compared to the placebo group [60]. A meta-analysis including 16 randomized controlled trials demonstrated that XBJ combined with routine treatment improved 28-day mortality in patients with sepsis [61]. In China, approximately 250,000 patients are treated with XBJ each year, and XBJ has been shown to be safe and well tolerated. Although XBJ is a potentially effective treatment for sepsis, additional research is still needed to understand its pharmacokinetics, interactions with antibiotics and pharmacological mechanisms of action.

Macrolides are a class of antimicrobials primarily against Gram-positive cocci and atypical pathogens. However, growing evidence shows that macrolides can be used as modulators of the host immune response in sepsis [62, 63]. Clarithromycin accelerated the resolution of ventilator-associated pneumonia (VAP) and weaning from mechanical ventilation in patients with sepsis and VAP [64]. Compared to the placebo group, sepsis patients in the clarithromycin group showed a decrease in serum IL-10 to TNF-α ratio and restoration of the balance between pro- and anti-inflammatory mediators [65]. Intravenous clarithromycin did not affect overall mortality in patients with sepsis, but clarithromycin may provide long-term survival benefits while also reducing the cost of hospitalization for patients [66, 67].

Enhance immunityImmunostimulatory factorG-CSF and GM-CSF

GM-CSF has been shown to reverse monocyte hyporesponsiveness in vitro and in vivo studies to increase blood monocyte levels, upregulate monocyte responsiveness, and increase HLA-DR expression‎, which is known to enhance antigen presentation and adaptive immune responses [68,69,70]. Premature neonates with sepsis or/and neutropenia treated with rhG-CSF adjuvant therapy were discharged with lower all-cause mortality and faster recovery of total leukocytes and ANC [71, 72]. Marlow et al. administered subcutaneous GM-CSF at a dose of 10 μg/kg daily for five days to infants less than 31 weeks of gestation and small-for-gestational-age (SGA), and showed no adverse outcomes during subsequent 2- and 5-year follow-up periods [73, 74]. However, a meta-analysis showed that a significant increase in the reversal rate of infection with G-CSF or GM-CSF therapy, patients patients with severe sepsis/septic shock did not have a benefit in 14- or 28-day mortality [75]. Meisel et al. treated patients with sepsis (monocytic HLA-DR [mHLA-DR] <8,000 monoclonal antibodies (mAb) per cell for 2 d) GM-CSF and observed a trend toward improved disease severity and restoration of mHLA-DR expression‎ and cytokine release [76]. G-CSF or GM-CSF application may lead to different outcomes in different stages of severe sepsis and is more applicable in patients with severe immunosuppression, making individualized and precise therapy guided by biomarkers based on immune status extremely important.

Tα1

Thymosin alpha 1 (Tα1) is an endogenous modulator of the innate and adaptive immune system. Tα1 plays an important biological role in activating and restoring sepsis in patients with a dysregulated immune response [77]. Tα1 may effectively improve the prognosis of patients with severe sepsis, improving HLA-DR expression‎, and reducing the incidence of secondary infections [78, 79]. In a meta-analysis of whether Tα1 was used in combination with UTI, the combination of UTI and Tα1 for severe sepsis reduced mortality at 28 and 90 days, whereas Tα1 alone reduced mortality only at 28 days [80]. Tα1 may be more effective as an immune modulator in patients with immunosuppressed states. A recent clinical trial (NCT02867267) in China further eval‎uated the efficacy and safety of Tα1 for sepsis, and recruitment in the study is now complete, and some information can be brought to light through this study.

IFN-γ

IFN-γ may be harmful during the pro-inflammatory phase of sepsis, which can stimulate monocytes and cause a vicious cycle of hyperinflammation [81]. However, IFN-exogenously administered would reverse markers of monocyte deactivation and ameliorate post-sepsis immunosuppression. 18 healthy male volunteers were treated with IFN-γ or GM-CSF or placebo after intravenous administration of Escherichia coli endotoxin, and IFN-γ partially reversed human immunoparalysis [82]. Patients with invasive Candida and/or Aspergillus infections regained partial immune function after IFN -γ treatment [83]. Classifying sepsis patients into independent immune classification strata based on ferritin and HLA-DR receptors/monocytes may improve the chances of successful immunotherapy trials in sepsis [84]. Patients with increased monocyte HLA-DR expression‎ after IFN-γ treatment early (<4 days) or late (>7 days) after a sepsis episode improved immune host defense in sepsis-induced immunosuppression [85]. IFN-γ may be a potential immunomodulatory therapy to reverse immunoparalysis in vivo in humans during sepsis.

IL-7

In several models of sepsis infection involving bacteria, fungi, and viruses, IL-7 treatment blocked CD4 and CD8T cell apoptosis, restored IFN- and immune effector cell recruitment, and improved mouse survival [86,87,88]. IL-7 levels are decreased in patients with sepsis [89]. IL-7 immunotherapy improved clinical symptoms, cleared the fungus, reversed lymphopenia, and reversed the profound loss of CD4+ and CD8+ T cells induced by sepsis [90,91,92]. Bidar et al. found that patients with severe COVID-19 admitted to the ICU exhibited severe T-cell depletion, which could be reversed in vitro by rhIL-7 [93]. In some cases, reports showed that IL-7 could be safely used in patients with severe COVID-19 and absolute lymphocytopenia and can benefit patients [94, 95]. IL-7 is safe and well tolerated and is a promising new immune-adjuvant therapy for sepsis.

IL-15

IL-15-deficient (IL-15 KO) mice are resistant to septic shock but IL-15 treatment exacerbates the severity of sepsis by activating NK cells and promoting IFN-γ production. Masafumi et al. showed that three subcutaneous injections of 1.5 μg IL-15 enhanced long-term T-cell depletion, increased NK and macrophage levels, and reduced mortality in mice [96]. The levels of plasma IL-15 were modestly increased and increased mortality in patients with severe lymphopenia compared to patients without lymphopenia [97]. Elevated serum IL-15 levels in patients with sepsis after emergency abdominal surgery were associated with prognosis and organ dysfunction, with non-survivors having significantly higher basal IL-15 levels than survivors, and this difference persisted throughout the course of the study [98]. Although IL-15 has a stimulatory effect on many immune cells, it may also promote systemic inflammation and organ damage in treating sepsis and has also been shown to have potentially toxic effects. Therefore, IL-15 needs further study as an immunotherapeutic agent in sepsis.

IL-33

IL-33 treatment played a protective activity against sepsis and also significantly reduced mortality in CLP septic mice [99,100,101]. IL-33 promotes inflammation by binding to its receptor ST2 (IL1RL1), expressed primarily on immune cells, making the IL-33/ST2 axis a bridge between immune system coordination and tissue damage [102]. Administration of IL-33Rα (ST2)-blocking antibody reduced IL-10 levels 24 hours after CLP, and a survival benefit was observed within 72 hours [103]. ST2 deletion affected septic dendritic cells’ phenotype and maturation and downregulated myeloid precursors and inflammatory NK cells [104]. During the immunosuppressive phase of sepsis, IL-33 levels increased and remained high for five months after recovery [105]. IL-33/ST2 is a novel axis associated with poor immune function in sepsis, and this axis may benefit patients as a personalized treatment for sepsis.

Immune checkpointPD-1/PD-L1

Upregulation of programmed cell death protein 1 (PD-1) on neutrophils may be associated with sepsis-induced immunosuppression [106]. Huang et al. have demonstrated that the survival of PD-1−/− mice is improved in a mouse model of sepsis induced by the cecal ligation-and-puncture procedure [107]. By blocking PD-L1 in animal models of sepsis, lymphocyte apoptosis was inhibited, macrophage dysfunction was reversed, and survival was improved [108, 109]. Treatment with anti-PD-1 and anti-PD-L1 specific antibodies prevented and/or reversed T-cell depletion and reversed immune dysfunction [110]. Our previous study showed that PD-1 expression‎ on memory CD8+ T cells identifies patients with a poor prognosis during sepsis [111]. In the first clinical eval‎uation in sepsis, the anti-PD-L1 immune checkpoint inhibitor appeared to be well tolerated and had the potential to restore immune status [112]. Immunotherapy has been shown to be effective in clinical trials for several types of malignancies, with FDA-approved anti-PD-1 blocking antibodies like nivolumab and pembrolizumab [113]. Nivolumab therapy also appeared to be well tolerated and safe in treating patients with sepsis or septic shock [114, 115]. Using nivolumab appears to improve selected immune markers such as ALC and monocyte human leukocyte antigen-DR subtype transcript levels. Immune checkpoints play an important role in sepsis, but immune checkpoint modulation strategies for sepsis still need to be further refined and personalized to balance the immune status of patients to prevent immune disorders.

CTLA-4

Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a coinhibitory cell surface protein expressed on T cells. Thus, overexpression‎ of CTLA-4 downregulates T cell activation and proliferation and suppresses the host immune response, preventing an overreaction of the immune system. Inoue et al. showed increased expression‎ of CTLA-4 on CD4, CD8, and regulatory T cells in a CLP mouse model, resulting in significantly improved survival at low doses and worsened survival at high doses when anti-CTLA-4 treatment was administered [116]. Chang et al. confirmed that immuno-adjuvant therapy with anti-PD-1, anti-PD-L1 and anti-CTLA-4 antibodies reversed sepsis-induced immunosuppression and improved survival in mice [117]. CTLA-4 is also highly expressed in CD4 T cells, CD8 T cells, and/or inhibitory receptors in monocytes from patients with sepsis [118, 119]. CTLA-4 genetic variants can be an important predictor of survival in sepsis patients, and precise anti-CTLA-4 therapy can be stratified according to CTLA-4 gene variants [120, 121].

TIM-3

T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) have been suggested to play an important role in maintaining immune homeostasis in sepsis. TIM-3 gene variants were associated with altered 28-day mortality and susceptibility to Gram-positive infections in patients with sepsis [122]. Upregulation of Tim-3 expression‎ is associated with poorer disease severity and prognosis in sepsis patients [123]. Blocking the Tim-3/Galectin-9 signalling axis inhibits NKT apoptosis in sepsis [123]. Huang et al. found that Tim-3 regulates sepsis-induced immunosuppression by inhibiting the NF-κB signalling pathway in CD4 T cells [124]. Blocking the immune checkpoint molecule Tim-3 may be a promising immunomodulatory strategy for the future clinical treatment of sepsis.

LAG-3

Lymphocyte activation gene 3 (LAG-3) is an immunoregulatory cell surface protein that negatively regulates T cell proliferation, activation, and homeostasis and is highly expressed in sepsis [118]. Genetic variation in LAG-3 is associated with altered disease severity and outcome in patients with sepsis, and 28-day mortality is significantly lower in LAG-3 rs951818 AA-homozygote patients than in C allele carriers [125]. LAG-3 knockout or anti–LAG-3 antibody blockade protected mice undergoing CLP from sepsis-associated immune dysfunction and maybe a new target for the treatment [126].

TIGIT

TIGIT is a novel coinhibitory molecule expressed on peripheral memory and regulatory CD4+T cells and NK cells. TIGIT was upregulated in Treg and NK cells of healthy and cancer sepsis mice [127]. Furthermore, the anti-TIGIT antibody reversed sepsis-induced T cell apoptosis in cancer septic mice and increased their 7-day survival in cancer septic mice. Expression‎ of TIGIT on T cells was significantly upregulated in sepsis patients, and in vitro blockade of TIGIT using an anti-TIGIT antibody restored the frequency of cytokine-producing T cells in sepsis patients [128]. Our previous study showed that the anti-TIGIT Ab reversed sepsis-induced T-cell apoptosis in cancer septic mice and resulted in a significant survival benefit [129].

VISTA

V-domain Ig suppressor of T cell activation (VISTA) has been identified as an immune checkpoint molecule that negatively regulates T-cell activation. Treatment with a high-affinity anti-VISTA antibody (clone MH5A) improved survival in septic mice and resulted in reduced lymphocyte apoptosis, decreased cytokine expression‎, and increased bacterial clearance [130]. Gray et al. showed that VISTA could regulate CD4+ Treg in response to an infectious attack during sepsis progression, exerting a protective effect and reducing septic morbidity/mortality [131]. VISTA also induces tolerance and transcriptional reprogramming of the anti-inflammatory program in macrophages to attenuate innate inflammation in vivo [132].

Immunoglobulin

Low levels of immunoglobulins are positively associated with the severity of critical illness and mortality in patients with sepsis [133]. A recent meta-analysis showed that the use of intravenous IgM-enriched immunoglobulins (IVIgGM) in adult sepsis patients may be associated with reduced mortality and shorter mechanical ventilation lengths [134]. However, in 2021, the Surviving Sepsis Campaign guidelines recommend against intravenous immunoglobulins in patients with sepsis or septic shock due to low quality of evidence [135]. Martinez et al. showed in a case-control analysis that treatment with IgGM in patients with sepsis significantly reduced 28-day mortality based on a validated selection of severity-matched comparators [136]. Patients with sepsis with low IgG levels (<670 mg/dL) had significantly lower mortality with intravenous immunoglobulin at 28 and 90 days [133]. Early administration (within 12 hours) of IgM- and IgA-enriched intravenous polyclonal immunoglobulins reduced the risk of in-ICU mortality in patients with septic shock caused by any pathogens [137]. There is a pressing need for more precise use of immunoglobulins in terms of patients’ selection, dosage, and timing in sepsis, which has to be verified by future clinical studies and may provide the greatest benefit.

Mesenchymal stem cell

Mesenchymal stem cells (MSCs) have attracted attention for sepsis treatment due to their anti-inflammatory and tissue regenerative potential to modulate innate and adaptive immune systems. MSCs can also act distantly on their targets through paracrine and extracellular vesicles (EVs) secretion-mediated pathways. Allogeneic adipose-derived MSCs (ADSCs) in CLP model mice at a dose of 2 × 107 cells/kg significantly reduced mortality, bacterial load, systemic inflammation, and multi-organ damage [138]. MSC-derived EVs attenuated pulmonary edema and inflammation in acute lung injury induced by an LPS-induced sepsis model in mice [139]. The use of umbilical cord-derived human MSCs for treating 15 patients with severe sepsis was well tolerated in the first phase 1 clinical trial [140]. Perlee et al. infused healthy subjects with allogeneic adipose MSCs (ASCs) followed by intravenous (2 ng/kg) LPS and found that high doses of MSCs were able to increase pro- and anti-inflammatory factors during the process [141]. Infusion of MSCs in patients with septic shock did not elevate cytokine levels and organ damage while dose-dependently attenuating pro-inflammatory cytokines [142]. MSCs may be a safe and effective strategy to treat sepsis, however, large-scale randomized controlled studies are required to convince present evidence.

Discussion and future perspectives

Sepsis is a dynamic disorder of dysregulated inflammatory and immune responses. Our previous study employed machine learning and bioinformatics to eval‎uate genome-wide gene expression‎ profiles in sepsis patients’ blood to construct a model that efficiently classifies sepsis into immunoparalysis and immunocompetent endotypes [143]. Seymour et al. sorted sepsis into four clinical phenotypes after a retrospective analysis of all clinical and laboratory variables in the electronic health records of 20,189 patients with sepsis using machine learning [144]. Baghela et al. used machine learning and data mining to analyze gene expression‎ signatures to classify patients with early sepsis into five distinct mechanistic endotypes [145]. However, there is still a large gap between the creation of AI algorithms and clinical implementation, and further prospective studies in multiple clinical settings are needed to improve the generalizability of these AI models.

The application of immune monitoring in treating patients with sepsis may facilitate early identification and diagnosis, allowing pre-emptive action to reduce the risk of secondary infection, organ dysfunction, and death. Using biomarkers to personalize and monitor therapy allows physicians to modulate the immunity of sepsis patients in real-time with selective immunotherapeutic agents. The following points may be noted for the use of immunotherapeutic agents in sepsis. Firstly, we need to be aware that unnecessary suppression of immune checkpoints can disrupt normal immune homeostasis and may cause side effects such as inflammation and autoimmune diseases. Therefore, the mechanisms of action of therapeutic agents and their adverse effects need to be precisely elucidated. Secondly, phenotypic analysis of the patient’s immune status and the development of a panel of biomarkers to enable targeted immunomodulatory interventions against sepsis-induced immune alterations. Finally, establishing rapid bedside testing, where targeted therapies will progress with the different stages of sepsis rather than being limited to treatments based on clinical presentation, makes sepsis treatment a prospective strategy.

Conclusion

Clinical trials have demonstrated that the use of “one-target” and “one-size-fits-all” treatment plans is unlikely to be effective for sepsis due to the intricate host response and the diverse pathophysiological changes. Therefore, it is important to develop an early warning system that can help us better understand the intricate biology, genetics, immunology, and clinical factors involved in sepsis to achieve accurate clinical phenotypes and precision treatment. Subsequent research endeavors should aim to enhance the comprehension of sepsis immune status, monitor immune progression, identify biochemical and immune risk factors, and explore biomarkers in sepsis patients. Furthermore, clarifying clinical and immune stratification and implementing strategies for AI-assisted clinical translation are essential for advancing sepsis management.

Data availability

There are no experimental datasets given that this is a review article that is prepared based on a literature review.

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