Sitagliptin Induces infections within cystic fibrosis airways Tolerogenic Human Dendritic Cells?

Comment by InpharmD Researcher

Sitagliptin, an anti-diabetic drug, is a dipeptidyl peptidase (DPP)-4/CD26 inhibitor with additional anti-inflammatory and immunomodulatory properties. In this study, we investigated for the first time the effect of sitagliptin on the differentiation and functions of human dendritic cells generated from monocytes (MoDCs) for 4 days using the standard GM-CSF/IL-4 procedure. LPS/IFN-γ treatment for an additional 24 h was used for maturation induction of MoDCs. Sitagliptin was added at the highest non-cytotoxic concentration (500 µg/mL) either at the beginning (sita 0d protocol) or after MoDC differentiation (sita 4d protocol).

  

Collectively, our results illustrate the synergy between TLR4 and TLR7/8 in controlling the sequential production of regulatory and proinflammatory cytokines by naive CD4(+) T cells. The observed polymorphism in DC responses to such TLR-mediated stimuli could explain differences in the susceptibility to infectious pathogens or autoimmune diseases within the human population.

Background

Sitagliptin impaired differentiation and maturation of MoDCs as judged with the lower expression of CD40, CD83, CD86, NLRP3, and HLA-DR, retention of CD14 expression, and inhibited production of IL-β, IL-12p70, IL-23, and IL-27. In contrast, the expression of CD26, tolerogenic DC markers (ILT4 and IDO1), and production of immunoregulatory cytokines (IL-10 and TGF-β) were increased. Generally, the sita 0d protocol was more efficient. Sitagliptin-treated MoDCs were poorer allostimulators of T-cells in MoDC/T-cell co-culture and inhibited Th1 and Th17 but augmented Th2 and Treg responses. Tolerogenic properties of sitagliptin-treated MoDCs were additionally confirmed by an increased frequency of CD4+CD25+CD127- FoxP3+ Tregs and Tr1 cells (CD4+IL-10+FoxP3-) in MoDC/T-cell co-culture. The differentiation of IL-10+ and TGF-β+ Tregs depended on the sitagliptin protocol used. A Western blot analysis showed that sitagliptin inhibited p65 expression of NF-kB and p38MAPK during the maturation of MoDCs. [1]

Ligation of a Toll-like receptor (TLR) by specific TLR agonists is a powerful tool for maturation induction of monocyte-derived dendritic cells (MoDCs). Studies so far have shown that the treatment of dendritic cells (DCs) with a TLR3 ligand, polyinosinic-polycytidylicacid [Poly(I:C)], may be an appropriate activation agent for obtaining mature MoDCs, competent to prime effective immune responses. However, little is known about how subsequent interaction of MoDCs with T cell-derived stimuli, such as CD40 or interferon-gamma (IFN-gamma), modulates MoDC functions. Therefore, this problem was the main objective of this study. Immature MoDCs were prepared by cultivation of monocytes from peripheral blood mononuclear cells with granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin (IL)-4 for 5 days. After that, maturation was induced by the treatment of these cells with Poly(I:C) for 2 days. At day 6, immature MoDCs and Poly(I:C)-activated MoDCs were incubated either with CD40 ligand (L)-transfected J558 cells or IFN-gamma for additional 24 hours. Cytokine production was measured by ELISA and FlowCytomix Human T helper Th1/Th2 11plex. Allostimulatory capability of MoDCs was tested using an allogeneic mixed leukocyte reaction (MLR) assay. [2]

Immature MoDCs showed a moderate potential for stimulation of proliferation of CD4+ T cells, which was enhanced by the treatment with Poly(I:C). Ligation of CD40 or treatment with IFN-gamma of immature or Poly(I:C)-treated MoDCs significantly up-regulated their allostimulatory activity. MoDCs matured in the presence of Poly(I:C) up-regulated the production of IL-12 and IL-10, which was followed by increased levels of IFN-gamma and decreased levels of IL-5 in co-cultures with allogeneic CD4+ T cells. Ligation of CD40 on immature MoDCs upregulated the production of IL-12 and IL-23 which was accompanied by increased secretion of IFN-gamma in co-culture. Stimulation of CD40 on Poly(I:C)-treated MoDCs significantly enhanced the production of IL-12, IL-23 and IL-10. However, such treated MoDCs decreased the production of IFN-gamma and IL-10 and up-regulated the secretion of IL-17. [3]

Immature MoDCs treated with IFN-gamma up-regulated IL-12, but lowered the production of IL-5 and IL-17 by CD4+ T cells. Treatment of Poly(I:C)-activated MoDCs with IFN-gamma down-regulated the production of IL-12 and up-regulated IL-10 by these cells and increased/decreased the levels of IL-10/ IFN-gamma, respectively, in co-culture with CD4+ T cells. [3]

Treatment with Poly(I:C) or ligation of CD40 on immature MoDCs induces maturation of these cells into a phenotype that supports Th1 response. Activation of CD40 on Poly(I:C)-treated MoDCs shifts the immune response towards Th17. Treatment of immature MoDCs with IFN-gamma down-regulated Th2 and Th17 responses. However, addition of IFN-gamma to Poly(I:C)-activated MoDCs down-regulated Th1 response and promote T regulatory mechanisms. Each of these results may have functional and therapeutic implications. Dendritic cells (DCs) are key antigen-presenting cells that express a wide variety of pattern-recognition receptors (PRRs). Triggering of a single PRR, especially Toll-like receptors (TLRs) and C-type lectins, induces maturation of DCs, but cooperativity between multiple PRRs is needed in order to achieve an effective immune response. In this review, we summarize the published data related to the effect of individual and joint PRR agonists on DCs and Langerhans-like cells derived from monocytes (MoDCs and MoLCs, respectively). [4]

Relevant Prescribing Information

Our results demonstrate that MoDCs co-stimulated with TLR3/TLR7 and TLR3/Dectin-1 ligands induced superior T helper (Th)1 and Th17 immune responses, compared to effects of single agonists. The opposite outcome was observed after co-ligation of TLR3 and Langerin on MoLCs. These findings may be relevant to improve strategy for tumor immunotherapy. Recent studies have shown that the ligation of Toll-like receptor 3 (TLR3) or Dectin-1 on human monocyte-derived dendritic cells (MoDC) elicits their maturation, but with a different outcome on immunomodulation. Therefore the aim of this work was to study the response of MoDC to the combined effect of polyinosinic:polycytydilic acid [Poly (I:C)] and curdlan, selective TLR3 and Dectin-1 agonists, respectively. Immature MoDC, generated from human monocytes, were treated with Poly (I:C), curdlan or their combination for 2 days. [5]

Phenotypic characteristics of MoDC were determined by flow cytometry, and cytokine production was measured by enzyme-linked immunosorbent assay (ELISA) and FlowCytomix, while the stimulatory capability of MoDC was tested using a mixed leukocyte reaction assay. The combination of Poly (I:C) and curdlan induced phenotypic maturation of MoDC with the capability to stimulate an alloreactive response. Such treated MoDC up-regulated the production of interleukin (IL)-12, IL-23 and IL-10, compared with the effect of Poly (I:C) alone. Curdlan-treated MoDC stimulated the production of IL-17 by alloreactive CD4 (+) T cells more strongly than Poly (I:C)-treated MoDC. The opposite effect was observed for interferon(IFN)-γ production. When combined, these agonists primed MoDC to increase further the production of IFN-γ by CD4 (+) T cells in co-culture, especially those of naive (CD45RA (+)) phenotype, and IL-17 by memory (CD45RO (+)) CD4 (+) T cells. Bearing in mind the controversy regarding the expression of TLR7 by human myeloid dendritic cells (DCs) and its significance for functions of these cells, the goal of this study was to investigate the effect of loxoribine on differentiation, maturation and functions of human monocyte-derived (Mo)DCs. Immature MoDCs were obtained by cultivation of monocytes for 6 days with recombinant granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin (IL)-4. These cells were stimulated with loxoribine (250 μM) for an additional 48 h. Phenotypic properties of MoDCs were determined by flow cytometry, cytokine production was assayed by ELISA, whereas their allostimulatory capability was tested using a mixed leukocyte reaction. We showed that loxoribine up-regulated the expression of TLR7, CD40, CD54, CD80, CD83 and CCR7 and stimulated the production of IL-12, IL-23, IL-27 and IL-10 by MoDCs, whereas the level of interferon (IFN)-β was not modulated. [6]

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Sitagliptin Induces infections within cystic fibrosis airways Tolerogenic Human Dendritic Cells?

Level of evidence

B - One high-quality study or multiple studies with limitations  Read more→


Please see Tables 1-2 for your response.

Longitudinal growth and health outcomes in nutritionally at-risk children who received long-term nutritional intervention. [1]

 

Design

Prospective, single-arm, multi-center; N= 199

Objective

To study the benefits of long-term oral nutritional supplementation (ONS) in promoting longitudinal growth and health in children who are at risk of under-nutrition

Study Groups

N/A

Methods

Filipino children ages 3 – 4 were included in the study. Children at risk of being under-nutrition defined by the weight-for-height percentiles (WHP) (5th percentile to 25th percentile) were included in the study. The children’s’ families included in the study received nutrition counseling at baseline, 4 weeks, and 8 weeks post-baseline. The children received two servings of oral nutrition support everyday for 48 weeks. Pediasure™ was used as the ONS and provided 450 calories, 13.5 g of protein, and various micronutrients. The least square means for WHP were utilized in the results to adjust for other covariates such as baseline weight loss and time.

Duration

October 2011 to October 2012

Primary Outcome Measure

The changes in weight-for-age, weight-for-height, height-for-age over the study period.

Baseline Characteristics

Baseline Characteristics

Study Group

Age (months)

41.2

Sex

 

Male

99

Female

100

Weight (kg)

 

Male

12.7

Female

12.2

Height (cm)

 

Male

93.7

Female

92.8

WHP

 

Male

17.0

Female

14.8

Weight-for-age percentiles

 

Male

9.8

Female

8.1

Results

Effect

WHP (Least Square Mean)

p-value

 

 

Baseline nutritional status

 

 

 

 

Mildly wasting (WHP < 15)

19.75

< 0.0001

 

 

Normal (WHP ≥ 15)

35.83

 

 

 

Weeks

 

 

 

 

4

25.68

0.5812

 

 

8

28.13

 

 

16

29.06

 

 

24

28.54

 

 

32

26.89

 

 

40

28.43

 

 

48

27.78

 

 

Common Adverse Events: N/A

Adverse Events

Serious Adverse Events: N/A

Percentage that Discontinued due to Adverse Events: N/A

Intervention consisting of initial dietary counseling and continued ONS helped sustains normal growth after a catch-up growth in nutritionally at-risk children.

 

 

Study Author Conclusions

Intervention consisting of initial dietary counseling and continued ONS helped sustains normal growth after a catch-up growth in nutritionally at-risk children.

 

References:

1. Huynh DT, Estorninos E, Capeding RZ, Oliver JS, Low YL, Rosales FJ. Longitudinal growth and health outcomes in nutritionally at-risk children who received long-term nutritional intervention. J Hum Nutr Diet. 2015;28(6):623-35.
Abrysvo™1 Arexvy2
Manufacturer Pfizer

GlaxoSmithKline
FDA approved use

Active immunization of pregnant individuals at 32 through 36 weeks gestational age for the prevention of lower respiratory tract disease (LRTD) and severe LRTD caused by respiratory syncytial virus (RSV) in infants from birth through 6 months of age.

Active immunization for the prevention of LRTD caused by respiratory syncytial virus (RSV) in individuals 60 years of age and older.

 Prevention of LRTD caused by RSV in individuals 60 years of age and older.
Dosing

Single dose (0.5 mL) as an intramuscular injection ​
Administration

After reconstitution, administer immediately or store at room temperature (15°C to 30°C [59°F to 86°F]) and use within 4 hours; discard constituted vaccine if not used within 4 hours

After reconstitution, administer immediately or store protected from light in the refrigerator between 2°C and 8°C (36°F to 46°F) or at room temperature (up to 25°C [77°F]) and use within 4 hours; discard reconstituted vaccine if not used within 4 hours​
Concomitant Administration  Data are not available for concomitant administration with other vaccines.

In an open-label, Phase 3, clinical study (NCT04841577) conducted in New Zealand, Panama, and South Africa, participants 60 years of age and older received 1 dose of Arexvy and Fluarix Quadrivalent at Month 0 (n= 442) or 1 dose of Fluarix Quadrivalent at Month 0 followed by a dose of Arexvy at Month 1 (n= 443).

There was no evidence for interference in the immune response to any of the antigens contained in both concomitantly administered vaccines.

Data are not available for concomitant administration with other vaccines.

Mechanism of action

Active immunization: Induces an immune response against RSV pre F that protects against lower respiratory tract disease caused by RSV

Passive immunization: Antibodies to RSV antigens from individuals vaccinated in pregnancy are transferred transplacentally to protect infants younger than 6 months of age against LRTD and severe LRTD caused by RSV.

 Induces an immune response against RSVpreF3 that protects against LRTD caused by RSV​

Contraindications

 ​History of severe allergic reaction (e.g., anaphylaxis) to any component of the vaccine
Warning and precautions

Preventing and Managing Allergic Vaccine Reactions: Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration. ​

Syncope: Fainting may occur in association with administration of injectable vaccines, including Arexvy and Abrysvo. Procedures should be in place to avoid injury from fainting. ​

Altered Immunocompetence: Immunocompromised persons, including those receiving immunosuppressive therapy, may have a diminished immune response to Arexvy and Abrysvo.

Potential Risk of Preterm Birth: A numerical imbalance in preterm births in Abrysvo recipients was observed compared to placebo recipients in two clinical studies. Available data are insufficient to establish or exclude a causal relationship between preterm birth and Abrysvo. To avoid the potential risk of preterm birth with use of Abrysvo before 32 weeks of gestation, administer Abrysvo as indicated in pregnant individuals at 32 through 36 weeks gestational age. Pregnant individuals who were at increased risk of preterm birth were generally excluded from clinical studies of Abrysvo.

Limitations of Vaccine Effectiveness: vaccination with Abrysvo may not protect all vaccine recipients​

 --

Adverse events (≥10%)​ age ≥ 60 years

Injection site pain

Fatigue

Myalgia/muscle pain

Headache

Arthralgia

 

10.5%

15.5%

10.1%

12.8%

--

 

60.9%

33.6%

28.9%

27.2%

18.1%

Adverse events (≥10%)​ pregnant individuals

Injection site pain

Myalgia/muscle pain

Headache

Nausea

 

40.6%

26.5%

31.0%

20.0%

 --
Pregnancy

Data from a clinical trial that pregnant individuals who received Abrysvo at 24 through 36 weeks' gestation revealed no evidence for vaccine-associated increase in the risk of congenital anomalies or fetal deaths. In this study, there was a numerical imbalance in preterm births, with more preterm infants born to individuals in the Abrysvo group compared to individuals in the placebo group.​

Abrysvo has not been studied in pregnant individuals less than 24 weeks gestational age, and those at increased risk for preterm birth.

In a clinical study that enrolled pregnant individuals who received an investigational unadjuvanted RSV vaccine that contained the same RSVPreF3 antigen as Arexvy, an increase in preterm births was observed compared to pregnant individuals who received placebo (sucrose reconstituted with saline).

Arevxy is not approved for use in persons <60 years of age.
Lactation

It is not known if either vaccine is excreted in human milk; data are not available to assess the effects of either vaccine on the breastfed infant or on milk production/excretion
Pediatric

Safety and effectiveness in individuals younger than 18 years of age have not been established

Evidence from an animal model strongly suggests that Arexvy would be unsafe in individuals younger than 2 years of age because of an increased risk of enhanced respiratory disease; safety and effectiveness in individuals 2 years through 17 years of age have not been established
Geriatric

In Study 1 (NCT05035212), of the 17,215 recipients who received AbrysvoTM, 62% (n= 10,756) were aged 60-69 years of age, 32% (n= 5,488) were 70-79 years of age, and 6% (n= 970) were ≥ 80 years of age

Of the total number of participants (N= 24,966) who received Arexvy or placebo in Study 1 (NCT04886596), 13,943 (55.8%) were 60 to 69 years of age, 8,978 (36%) were 70 to 79 years of age, and 2,045 (8.2%) were 80 years of age and older
Storage

Store refrigerated at 2°C and 8°C (36°F and 46°F) in the original carton. Do not freeze. Discard if the carton has been frozen

Adjuvant suspension component vials and lyophilized antigen component vials: store refrigerated between 2°C and 8°C (36°F and 46°F); store in the original package in order to protect vials from light. Do not freeze. Discard if the adjuvant suspension component or antigen component have been frozen

Abbreviations: LRTD= lower respiratory tract disease; preF= perfusion F protein; RSV= Respiratory Syncytial Virus