Rapid Cytokine Production Research Articles

Liver type 1 innate lymphoid cells undergo apoptosis in murine models of macrophage activation syndrome and are dispensable for disease.

Macrophage activation syndrome (MAS) exemplifies a severe cytokine storm disorder with liver inflammation. In the liver, classical natural killer (cNK) cells and liver-resident type 1 innate lymphoid cells (ILC1s) dominate the ILC population. Thus far, research has primarily focused on the corresponding role of cNK cells. Considering the liver inflammation and cytokine storm in MAS, liver-resident ILC1s represent an interesting population to explore due to their rapid cytokine production upon environmental triggers. By utilizing a Toll-like receptor (TLR)9- and TLR3:4-triggered MAS model, we showed that ILC1s highly produce IFN-γ and TNF-α. However, activated ILC1s undergo apoptosis and are strongly reduced in numbers, while cNK cells resist inflammation-induced apoptosis. Signs of mitochondrial stress suggest that this ILC1 apoptosis may be driven by inflammation-induced mitochondrial impairment. To study whether early induction of highly cytokine-producing ILC1s influences MAS development, we used Hobit KO mice due to their paucity of liver ILC1s but unaffected cNK cell numbers. Nevertheless, neither the severity of MAS features nor the total inflammatory cytokine levels were affected in these Hobit KO mice, indicating that ILC1s are dispensable for MAS pathogenesis. Collectively, our data demonstrate that ILC1s undergo apoptosis during TLR-triggering and are dispensable for MAS pathogenesis.

Correlative biomarker analyses for optimal therapeutic dose determination of ABBV-383, a B-cell maturation antigen (BCMA) x CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma (RRMM).

7532 Background: ABBV-383 is a BCMA x CD3 bispecific antibody with 2 high-affinity BCMA-binding domains and a low-affinity CD3 engaging arm that has been shown to decrease the negative impact of soluble BCMA (sBCMA) and drive sustained T-cell activation with reduced cytokine release in preclinical models of MM. Here, we describe correlative biomarker results of baseline and longitudinal sBCMA levels and immune profiles in the ongoing first-in-human trial that supports 60 mg Q4W as the optimal therapeutic dose of ABBV-383 monotherapy. Methods: Peripheral blood and serum samples from patients with RRMM enrolled in the phase 1 open-label, dose-expansion study (NCT03933735) who received ABBV-383 at 20, 40, or 60 mg Q3W or 60 mg Q4W were collected at baseline (post-dexamethasone, pre–ABBV-383), on treatment, and at disease progression. Samples were analyzed by flow cytometry for immune cell populations, Luminex for cytokines, and electrochemiluminescence ligand binding for sBCMA. Results: Median sBCMA levels at baseline were highly variable among patients, but did not associate with clinical response (≥ partial response [PR]) to ABBV-383 at the selected optimal dose level of 60 mg Q4W (<PR: 244.7 ng/mL; ≥PR: 52.2 ng/mL; P=0.13). Reduction in sBCMA levels over time associated with clinical response (Cmin at cycle 5: <PR, 244.7 ng/mL; ≥PR, 4.7 ng/mL; P=0.04). ABBV-383 treatment led to a rapid and transient increase of proinflammatory cytokines, including IL-6, IL-8, IL-10, TNF-α (Cmax within cycle 1: 29, 349.5, 1375, 456.5 pg/mL, respectively), and promoted T-cell redistribution (89% reduction of CD8+ T cells from periphery), activation (1.9-fold increase in CD69+CD8+ T cells), and proliferation (2-fold increase in Ki67+CD8+ T cells) within cycle 1 in 60-mg Q4W-treated patients. The frequency of baseline CD8+ T-cell exhaustion (PD-1/TIM3) did not impact clinical response at the optimal dose level of 60 mg Q4W ABBV-383 (<PR: 3.5%; ≥PR: 3.9%; P=0.9). Peak induction levels of proinflammatory cytokines during cycle 1 correlated with occurrence of cytokine release syndrome (≥G1) as well as clinical response across dose levels. Conclusions: High-avidity BCMA binding coupled to low-affinity T-cell engagement distinguishes the resulting mechanism of action for ABBV-383. Responses to 60 mg Q4W ABBV-383 were independent of baseline sBCMA levels and resulted in rapid and transient proinflammatory cytokine production that promoted robust T-cell redistribution, activation, and proliferation, indicating that the optimal dose of ABBV-383 maximizes its clinical potential as a convenient, safe, and effective therapy for MM. Clinical trial information: NCT03933735 .

Glycolipid antigen recognition by invariant natural killer T cells and its role in homeostasis and antimicrobial responses.

Due to the COVID-19 pandemic, the importance of developing effective vaccines has received more attention than ever before. To maximize the effects of vaccines, it is important to select adjuvants that induce strong and rapid innate and acquired immune responses. Invariant natural killer T (iNKT) cells, which constitute a small population among lymphocytes, bypass the innate and acquired immune systems through the rapid production of cytokines after glycolipid recognition; hence, their activation could be used as a vaccine strategy against emerging infectious diseases. Additionally, the diverse functions of iNKT cells, including enhancing antibody production, are becoming more understood in recent years. In this review, we briefly describe the functional subset of iNKT cells and introduce the glycolipid antigens recognized by them. Furthermore, we also introduce novel vaccine development taking advantages of iNKT cell activation against infectious diseases.

Rebuilding the myocardial microenvironment to enhance mesenchymal stem cells-mediated regeneration in ischemic heart disease.

Mesenchymal stem cells (MSCs) are naturally-derived regenerative materials that exhibit significant potential in regenerative medicine. Previous studies have demonstrated that MSCs-based therapy can improve heart function in ischemia-injured hearts, offering an exciting therapeutic intervention for myocardial ischemic infarction, a leading cause of worldwide mortality and disability. However, the efficacy of MSCs-based therapies is significantly disturbed by the myocardial microenvironment, which undergoes substantial changes following ischemic injury. After the ischemic injury, blood vessels become obstructed and damaged, and cardiomyocytes experience ischemic conditions. This activates the hypoxia-induced factor 1 (HIF-1) pathway, leading to the rapid production of several cytokines and chemokines, including vascular endothelial growth factor (VEGF) and stromal-derived factor 1 (SDF-1), which are crucial for angiogenesis, cell migration, and tissue repair, but it is not sustainable. MSCs respond to these cytokines and chemokines by homing to the injured site and participating in myocardial regeneration. However, the deteriorated microenvironment in the injured myocardium poses challenges for cell survival, interacting with MSCs, and constraining their homing, retention, and migration capabilities, thereby limiting their regenerative potential. This review discusses how the deteriorated microenvironment negatively affects the ability of MSCs to promote myocardial regeneration. Recent studies have shown that optimizing the microenvironment through the promotion of angiogenesis can significantly enhance the efficacy of MSCs in treating myocardial infarction. This approach harnesses the full therapeutic potential of MSCs-based therapies for ischemic heart disease.

Concomitant assessment of PD-1 and CD56 expression identifies subsets of resting cord blood Vδ2 T cells with disparate cytotoxic potential

Vγ9Vδ2 T lymphocytes are programmed for broad antimicrobial responses with rapid production of Th1 cytokines even before birth, and thus thought to play key roles against pathogens in infants. The process regulating Vδ2 cell acquisition of cytotoxic potential shortly after birth remains understudied. We observed that perforin production in cord blood Vδ2 cells correlates with phenotypes defined by the concomitant assessment of PD-1 and CD56. Bulk RNA sequencing of sorted Vδ2 cell fractions indicated that transcripts related to cytotoxic activity and NK function are enriched in the subset with the highest proportion of perforin+ cells. Among differentially expressed transcripts, IRF8, previously linked to CD8 T cell effector differentiation and NK maturation, has the potential to mediate Vδ2 cell differentiation towards cytotoxic effectors. Our current and past results support the hypothesis that distinct mechanisms regulate Vδ2 cell cytotoxic function before and after birth, possibly linked to different levels of microbial exposure.

Updated Safety and Efficacy Results of Abbv-383, a BCMA x CD3 Bispecific T-Cell Redirecting Antibody, in a First-in-Human Phase 1 Study in Patients with Relapsed/Refractory Multiple Myeloma

Updated Safety and Efficacy Results of Abbv-383, a BCMA x CD3 Bispecific T-Cell Redirecting Antibody, in a First-in-Human Phase 1 Study in Patients with Relapsed/Refractory Multiple Myeloma

The intestinal γδ T cells: functions in the gut and in the distant organs.

Located in the frontline against the largest population of microbiota, the intestinal mucosa of mammals has evolved to become an effective immune system. γδ T cells, a unique T cell subpopulation, are rare in circulation blood and lymphoid tissues, but rich in the intestinal mucosa, particularly in the epithelium. Via rapid production of cytokines and growth factors, intestinal γδ T cells are key contributors to epithelial homeostasis and immune surveillance of infection. Intriguingly, recent studies have revealed that the intestinal γδ T cells may play novel exciting functions ranging from epithelial plasticity and remodeling in response to carbohydrate diets to the recovery of ischemic stroke. In this review article, we update regulatory molecules newly defined in lymphopoiesis of the intestinal γδ T cells and their novel functions locally in the intestinal mucosa, such as epithelial remodeling, and distantly in pathological setting, e.g., ischemic brain injury repair, psychosocial stress responses, and fracture repair. The challenges and potential revenues in intestinal γδ T cell studies are discussed.

Innate immune responses to enteric Escherichia colidictate neonatal sepsis outcomes

Abstract Late-onset neonatal sepsis (LOS), a leading cause of neonatal death, can result from pathogenic bacteria disseminating to the bloodstream from the intestinal microbiota. E. coliis the second most commonly isolated pathogen causing LOS. During sepsis, there are significant immune discrepancies between infants and adults, including elevated IL-6 levels in neonates, demonstrating the need for age-specific research. We have developed a murine model of LOS that uses clinical isolates of gut-resident E. coli, which results in rapid pro-inflammatory cytokine production within 6 hours and neonatal mortality within 2–3 days post-infection. Not all enteric E. coliresults in inflammation and mortality, and we have classified isolates as “commensal” or “pathogenic”. TLR4−/− mice infected with pathogenic E. colihave a delayed mortality to sepsis, suggesting innate bacterial recognition is required for acute inflammation. To further determine the source of this delay, we have begun investigating signaling pathways during bacterial infection. We found the immune signaling pathway NFκB/AP1 is consistently activated in murine macrophages by commensal and pathogenic bacterial strains. However, only pathogenic bacteria induce elevated IL-6 production by murine macrophages. Interestingly, this response required live bacteria, suggesting lipopolysaccharide alone from E. coliis not sufficient to recapitulate LOS inflammation. Our future directions will explore alternative signaling pathways that are activated uniquely during pathogenic infection and induce a robust inflammatory response. Through this work, we will determine the consequence of specific pro-inflammatory cytokines in neonatal mice during pathogenic infection. Research supported by R03 DK122187.

Tocilizumab for Severe COVID-19 Infection and Multisystem Inflammatory Syndrome in Adults and Children.

Coronavirus disease 2019 (COVID-19) rapidly emerged as a global pandemic, placing imminent stress and burden on healthcare resources and workers worldwide. Many patients who present with a severe COVID-19 infection are at high risk of developing severe acute respiratory distress syndrome (ARDS), leading to a vast number of patients requiring mechanical ventilation and a high mortality rate. Similar to Middle East respiratory syndrome, COVID-19 demonstrates an initial viral replication phase that manifests as a variety of symptoms typically flu-like in nature, followed by a profound inflammatory response leading to rapid production of cytokines and uncontrolled inflammation. There have also been many cases of COVID-19 in pediatric patients presenting with elevated inflammatory markers and multisystem involvement labeled as a multisystem inflammatory syndrome (MIS-C) by the world health organization (WHO). The recent treatment of systemic inflammatory response to COVID-19 targets the secondary phase involving cytokine release syndrome. The detrimental effects of IL-6 can be profound and elevated levels are associated with a higher mortality rate and mechanical ventilation. Tocilizumab is an IL-6 inhibitor most widely investigated to target cytokine storm syndrome. Since June 2021, the FDA enacted an emergency use authorization for tocilizumab in the treatment of COVID-19. Several clinical trials have investigated tocilizumab combined with corticosteroids for treating severe ARDS associated with COVID-19. An increasing amount of evidence suggests that targeting the cytokine storm syndrome related to COVID-19 can lead to improved outcomes, especially in those patients requiring mechanical ventilation and with a critical illness. Additional studies are warranted to further look at the positive effects of tocilizumab in the COVID-19 population while additionally defining possible adverse effects.

Influenza-Induced CD103+ T Resident Memory Cells Exhibit Enhanced Functional Avidity over CD103- Memory T Cells in the Mediastinal Lymph Node.

Influenza virus–specific tissue-resident memory CD8 T cells (Trms) targeting conserved viral proteins provide strain-transcending heterosubtypic immunity to infection. Trms in the lung combat reinfection through rapid cytolytic function and production of inflammatory cytokines to recruit other immune cells. Influenza-specific Trms are also generated in the lung draining mediastinal lymph node (mLN) and can provide immunity to heterologous virus infection in this tissue, although their role in combating influenza infection is less well defined. Functional avidity, a measure of T cell sensitivity to Ag stimulation, correlates with control of viral infection and may be important for immune detection of recently infected cells, when low numbers of surface peptide–MHC complexes are displayed. However, the functional avidity of influenza-specific Trms has not been previously compared with that of other memory CD8 T cell subsets. In this article, a methodology is presented to compare the functional avidity of CD8 T cell subsets across murine tissues, with a focus on influenza-specific mLNs compared with splenic CD8 T cells, by stimulating both populations in the same well to account for CD8 T cell–extrinsic variables. The functional avidity of influenza-specific mLN effector CD8 T cells is slightly increased relative to splenic effector CD8 T cells. However, CD103+ mLN Trms display increased functional avidity compared with splenic memory CD8 T cells and CD103− memory CD8 T cells within the mLN. In contrast, lung-derived CD103+ Trms did not exhibit enhanced functional avidity. mLN CD103+ Trms also exhibit increased TCR expression, providing a potential mechanism for their enhanced functional avidity.

Third generation CAR T cells form polyfunctional long-lived memory and protect from solid-tumor relapse in an immunocompetent murine model

Abstract Effector CAR T cell persistence and transition to memory have been widely associated with long-term protection from hematological tumor relapse. In the context of solid tumors, anti-tumor T cell exhaustion in the tumor microenvironment (TME) leads to T cell dysfunction and impaired memory formation. However, in solid tumor models a vast number of infused CAR T cells traffic to lymphoid organs (such as spleen and nondraining lymph nodes), which are bereft of CAR-antigen. The fate of these CAR T cells which have undergone ex vivo activation, viral transduction, and expansion regimens prior to transfer back into patients remains unclear. Using a third generation CAR targeting human(h)CD19t, and syngeneic murine tumor lines expressing hCD19t tumor-associated antigen, we show that CAR T cells residing in antigen-free sites of tumor-bearing immunocompetent mice transition to fully functional memory cells. Using viral infection-induced memory T cells as a benchmark, memory CAR T cells displayed hallmark memory characteristics including homeostatic proliferation, rapid polyfunctional cytokine production upon restimulation, and secondary expansion in response to cognate antigenic stimulation. Finally, memory CAR T cells in naive mice, or in mice with primary tumor remission, were protected against lethal rechallenge with heterologous hCD19t-expressing tumors. Results from this study are among the first to directly compare canonical virus-induced memory T cells with memory CAR T cells, and provide valuable insight into the characteristics and function of memory CAR T cells in an immunocompetent model for solid tumors. Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number F32CA265056, and the Pediatric Cancer Research Foundation

Human MAIT Cells Respond to Staphylococcus aureus with Enhanced Anti-Bacterial Activity.

Mucosal-Associated Invariant T (MAIT) cells have been shown to play protective roles during infection with diverse pathogens through their propensity for rapid innate-like cytokine production and cytotoxicity. Among the potential applications for MAIT cells is to defend against Staphylococcus aureus, a pathogen of serious clinical significance. However, it is unknown how MAIT cell responses to S. aureus are elicited, nor has it been investigated whether MAIT cell cytotoxicity is mobilized against intracellular S. aureus. In this study, we investigate the capacity of human MAIT cells to respond directly to S. aureus. MAIT cells co-cultured with dendritic cells (DCs) infected with S. aureus rapidly upregulate CD69, express IFNγ and Granzyme B and degranulate. DC secretion of IL-12, but not IL-18, was implicated in this immune response, while TCR binding of MR1 is required to commence cytokine production. MAIT cell cytotoxicity resulted in apoptosis of S. aureus-infected cells, and reduced intracellular persistence of S. aureus. These findings implicate these unconventional T cells in important, rapid anti-S. aureus responses that may be of great relevance to the ongoing development of novel anti-S. aureus treatments.

Methylprednisolone Protects Severe Acute Pancreatitis And Pancreatitis-Associated Acute Lung Injury in Mice By Inhibiting NLRP3 Inflammasome Through NF-κB

In serve acute pancreatitis (SAP), the rapid production and releasing of inflammatory cytokines can cause local and systemic excessive inflammation, especially pancreatitis-associated acute lung injury (P-ALI). Methylprednisolone (MP) is a synthetic corticosteroid with potent anti-inflammatory and antioxidant properties used as therapy for a variety of diseases. In this study, we found MP, used in the early phase of SAP, decreased the levels of IL-1β and TNF-α in serum and peritoneal lavage fluids (PLF), reduced the level of serum amylase and the expression of MPO in lung tissue, attenuated the pathological injury of the pancreas and lungs in a dosedependent manner. The expression of NLRP3 and IL-1β in pancreas and lungs was down regulated significantly depending on the MP concentration. In vitro, MP reduced the levels of IL-1β and TNF-α by down regulating the expression of NLRP3, IL-1β and p-NF-κB in isolated peritoneal macrophages. Taken together, MP can attenuate the injury of pancreas and lungs, and the inflammatory response in SAP mice by down regulating the activation of NF-κB and the NLRP3 inflammasome.

Sepsis leads to lasting changes in phenotype and function of memory CD8 T cells.

The global health burden due to sepsis and the associated cytokine storm is substantial. While early intervention has improved survival during the cytokine storm, those that survive can enter a state of chronic immunoparalysis defined by transient lymphopenia and functional deficits of surviving cells. Memory CD8 T cells provide rapid cytolysis and cytokine production following re-encounter with their cognate antigen to promote long-term immunity, and CD8 T cell impairment due to sepsis can pre-dispose individuals to re-infection. While the acute influence of sepsis on memory CD8 T cells has been characterized, if and to what extent pre-existing memory CD8 T cells recover remains unknown. Here, we observed that central memory CD8 T cells (TCM) from septic patients proliferate more than those from healthy individuals. Utilizing LCMV immune mice and a CLP model to induce sepsis, we demonstrated that TCM proliferation is associated with numerical recovery of pathogen-specific memory CD8 T cells following sepsis-induced lymphopenia. This increased proliferation leads to changes in composition of memory CD8 T cell compartment and altered tissue localization. Further, memory CD8 T cells from sepsis survivors have an altered transcriptional profile and chromatin accessibility indicating long-lasting T cell intrinsic changes. The sepsis-induced changes in the composition of the memory CD8 T cell pool and transcriptional landscape culminated in altered T cell function and reduced capacity to control L. monocytogenes infection. Thus, sepsis leads to long-term alterations in memory CD8 T cell phenotype, protective function and localization potentially changing host capacity to respond to re-infection.

NKT and NKT-like Cells in Autoimmune Neuroinflammatory Diseases-Multiple Sclerosis, Myasthenia Gravis and Guillain-Barre Syndrome.

NKT cells comprise three subsets—type I (invariant, iNKT), type II, and NKT-like cells, of which iNKT cells are the most studied subset. They are capable of rapid cytokine production after the initial stimulus, thus they may be important for polarisation of Th cells. Due to this, they may be an important cell subset in autoimmune diseases. In the current review, we are summarising results of NKT-oriented studies in major neurological autoimmune diseases—multiple sclerosis, myasthenia gravis, and Guillain-Barre syndrome and their corresponding animal models.

Attenuation of COVID-19-induced cytokine storm in a young male patient with severe respiratory and neurological symptoms

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), the etiological agent of coronavirus disease 2019 (COVID-19), produces protean manifestations and causes indiscriminate havoc in multiple organ systems. This rapid and vast production of proinflammatory cytokines contributes to a condition termed cytokine storm. A 35-year-old, otherwise healthy, employed, male patient was tested positive for COVID-19. He was admitted to the hospital on disease day 10 due to retarded verbal reactions and progressive delirium. On account of these conditions and the need for noninvasive/invasive ventilation, a combination treatment with baricitinib and remdesivir in conjunction with standard of care was initiated. The cytokine storm was rapidly blocked, leading to a vast pulmonary recovery with retarded recovery of the central nervous system. We conclude that the rapid blockade of the COVID-19-induced cytokine storm should be considered of avail as a principle of careful decision-making for effective recovery.

The Invariant NKT Cell Response Has Differential Signaling Requirements during Antigen-Dependent and Antigen-Independent Activation.

Invariant NKT (iNKT) cells are an innate-like population characterized by their recognition of glycolipid Ags and rapid cytokine production upon activation. Unlike conventional T cells, which require TCR ligation, iNKT cells can also be stimulated independently of their TCR. This feature allows iNKT cells to respond even in the absence of glycolipid Ags, for example, during viral infections. Although the TCR-dependent and -independent activation of iNKT cells have been relatively well established, the exact contributions of IL-12, IL-18, and TLRs remain unclear for these two activation pathways. To definitively investigate how these components affect the direct and indirect stimulation of iNKT cells, we used mice deficient for either MyD88 or the IL-12Rβ2 in the T cell lineage. Using these tools, we demonstrate that IL-12, IL-18, and TLRs are completely dispensable for the TCR activation pathway when a strong agonist is used. In contrast, during murine CMV infection, when the TCR is not engaged, IL-12 signaling is essential, and TLR signaling is expendable. Importantly, to our knowledge, we discovered an intrinsic requirement for IL-18 signaling by splenic iNKT cells but not liver iNKT cells, suggesting that there might be diversity, even within the NKT1 population.

Immune recognition of phosphoantigen-butyrophilin molecular complexes by γδ T cells.

Gamma-delta (γδ) T cells are an important component of the immune system. They are often enriched in non-lymphoid tissues and exhibit diverse functional attributes including rapid activation, cytokine production, proliferation, and acquisition of cytotoxicity following both TCR-dependent and TCR-independent stimulation, but poor capacity for immunological memory. They can detect a broad range of antigens, although typically not peptide-MHC complexes in contrast to alpha-beta (αβ) T cells. In humans, a prominent population of γδ T cells, defined as Vγ9Vδ2+ cells, reacts to small phosphorylated non-peptide "phosphoantigens" (pAgs). The molecular mechanism underpinning this recognition is poorly defined, but is known to involve butyrophilin family members and appears to involve indirect pAg recognition via alterations to butyrophilin molecular complexes. In this review, we discuss recent advances in our understanding of pAg recognition by γδ T cells including the role of butyrophilins and in particular, a newly described role for butyrophilin 2A1.

Hyper-Inflammatory Monocyte Activation Following Endotoxin Exposure in Food Allergic Infants.

Several recent studies have reported a key role for innate cell hyper-responsiveness in food allergy. This has predominantly been observed in early life, with evidence that innate immune function may return to baseline if food allergy resolves in later childhood. Hallmarks of hyper-responsiveness include increased circulating frequency of monocytes and altered innate cell cytokine responses to in vitro exposure with bacterial endotoxin. These features mirror the defining signatures of trained innate immunity, seen in other complex diseases. In this study, detailed immune cell and cytokine profiling was performed on peripheral blood mononuclear cells at baseline from 27 1 year old infants in the HealthNuts cohort (n = 16 egg allergic and n = 11 non-allergic healthy controls) and following monocyte stimulation. We show that egg allergic infants have increased frequency of circulating monocytes, reduced numbers of regulatory CD4 T cells and increased monocyte: CD4 T cell ratios relative to healthy controls. Monocytes from both egg allergic and non-allergic infants responded to endotoxin stimulation with rapid cytokine production and downregulation of the surface receptor CD16, however monocytes from egg allergic infants were hyper-responsive, producing significantly more inflammatory cytokines (TNFα, IL-6, IL-1β, IL-8) and innate cell recruiting factors (MIP-1α) than healthy controls. This work indicates that monocytes of food allergic infants are programmed to a hyper-inflammatory phenotype and that the development of food allergy may be associated with trained immunity in early life.

A rapid, sensitive, and reproducible in vivo PBMC humanized murine model for determining therapeutic-related cytokine release syndrome.

Immunotherapy is a powerful treatment strategy being applied to cancer, autoimmune diseases, allergies, and transplantation. Although therapeutic monoclonal antibodies (mAbs) have demonstrated significant clinical efficacy, there is also the potential for severe adverse events, including cytokine release syndrome (CRS). CRS is characterized by the rapid production of inflammatory cytokines following delivery of therapy, with symptoms ranging from mild fever to life‐threating pathology and multi‐organ failure. Overall there is a paucity of models to reliably and accurately predict the induction of CRS by immune therapeutics. Here, we describe the development of a humanized mouse model based on the NOD‐scid IL2rgnull (NSG) mouse to study CRS in vivo. PBMC‐engrafted NSG, NSG‐MHC‐DKO, and NSG‐SGM3 mice were used to study cytokine release in response to treatment with mAb immunotherapies. Our data show that therapeutic‐stimulated cytokine release in these PBMC‐based NSG models captures the variation in cytokine release between individual donors, is drug dependent, occurs in the absence of acute xeno‐GVHD, highlighting the specificity of the assay, and shows a robust response following treatment with a TGN1412 analog, a CD28 superagonist. Overall our results demonstrate that PBMC‐engrafted NSG models are rapid, sensitive, and reproducible platforms to screen novel therapeutics for CRS.