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ID PMID Title PublicationDate abstract
31404701 Macrophages with regulatory functions, a possible new therapeutic perspective in autoimmun 2019 Oct Macrophages are pivotal cells involved in chronic inflammatory and autoimmune diseases. In fact, during these diseases, activated macrophages may play a critical role, promoting the inflammation as well as mediating the damage resolution. This dichotomy is referred to two end-stage phenotypes of macrophages, conventionally known as M1 and M2, playing a pro-inflammatory and anti-inflammatory role, respectively. The M1 macrophages are the mainly subset involved during inflammatory processes, producing pro-inflammatory mediators. Conversely, the M2 macrophages are proposed to contribute to the resolution phase of inflammation, when cells with pro-resolving property are recruited and activated. In fact, this subset of macrophages may activate regulatory T lymphocytes, which play a critical role in the maintenance of peripheral tolerance and preventing the occurrence of autoimmune diseases. On these bases, the polarization toward the M2 phenotype could play a therapeutic role for autoimmune diseases. In this Review we discussed the characteristic of M1 and M2 macrophages, focusing on the immunoregulatory role of M2 cells and their potential ability to control the inflammation and to promote the immunological tolerance.
30886736 Percentage of progressors in imaging: can we ignore regressors? 2019 Stopping or preventing structural progression is a goal common to all inflammatory rheumatic diseases. Imaging may capture structural progression across diseases, but is susceptible to measurement error. Progression can be analysed as a continuous change score over time (eg, mean change of the van der Heijde-modified Sharp score) or as a binary change score (eg, percentage of progressors according to the modified New York criteria). Here, we argue that the former takes measurement error into account while the latter ignores it, which may lead to spurious conclusions. We will argue that assumptions underlying commonly used binary definitions of progression are false and we propose a method that incorporates (inevitable) measurement error.
30853960 Thioredoxin Modulates Protein Arginine Deiminase 4 (PAD4)-Catalyzed Citrullination. 2019 Protein citrullination is a post-translational modification catalyzed by the protein arginine deiminases (PADs). This modification plays a crucial role in the pathophysiology of numerous autoimmune disorders including RA. Recently, there has been a growing interest in investigating physiological regulators of PAD activity to understand the primary cause of the associated disorders. Apart from calcium, it is well-documented that a reducing environment activates the PADs. Although the concentration of thioredoxin (hTRX), an oxidoreductase that maintains the cellular reducing environment, is elevated in RA patients, its contribution toward RA progression or PAD activity has not been explored. Herein, we demonstrate that hTRX activates PAD4. Kinetic characterization of PAD4 using hTRX as the reducing agent yielded parameters that are comparable to those obtained with a routinely used non-physiological reducing agent, e.g., DTT, suggesting the importance of hTRX in PAD regulation under physiological conditions. Furthermore, we show that various hTRX mutants, including redox inactive hTRX variants, are capable of activating PAD4. This indicates a mechanism that does not require oxidoreductase activity. Indeed, we observed non-covalent interactions between PAD4 and hTRX variants, and propose that these redox-independent interactions are sufficient for hTRX-mediated PAD4 activation.
30723598 Survival Rate on a 10-Year Follow-Up of Total Wrist Replacement Implants: A 23-Patient Cas 2019 Feb Background  According to current literature, the estimated average survival rate for Remotion, the total wrist implants, is above 90% on an 8-year follow-up. We examined our series of Remotion to calculate its survival rate on a 10-year follow-up. Case Description  A total of 23 cases of total wrist implants were reviewed. The case series included 22 patients, 18 females and 4 males, of an average age of 55 years. The case series included 19 inflammatory rheumatic diseases, 3 Kienböck disease, and 1 posttraumatic arthrosis. Conclusion  The average survival rate of our case series was 95.7% on a 4-year follow-up, 91.3% on a 6-year follow-up, and 69% on a 10-year follow-up. On our review, the QuickDASH score, pain, wrist extension range of motion, and grip strength were improved postoperatively. No difference was shown between preoperative and postoperative values for wrist flexion, pronation, and supination. The case series included a septic case, treated by arthrodesis, and three total wrist implants displacements, two of which were treated by carpal implant, and the remaining one was treated by arthrodesis. Clinical Relevance  The survival rate of the total wrist replacement implant Remotion was estimated to be 69%.
30719064 Moxibustion of Zusanli (ST36) and Shenshu (BL23) Alleviates Cartilage Degradation through 2019 Rheumatoid arthritis (RA) is a systemic and chronic autoimmune inflammatory disease characterized by severe synovial hyperplasia associated with progressive cartilage degradation. Due to the severe pain and disability caused by RA, effective therapeutic strategies that could simultaneously alleviate the inflammatory response and delay the disease progression are urgently needed. As a major alternative therapy in traditional Chinese medicine, moxibustion has been demonstrated that it could reduce the chronic inflammatory responses of a series of musculoskeletal diseases; however, whether moxibustion has protective effects on RA is still unclear. To investigate the effects of moxibustion on RA, moxibustion was applied to Zusanli (ST36) and Shenshu (BL23) acupoints in a RA rabbit model. HE staining of articular cartilage showed that moxibustion alleviated the cartilage degradation and bone destruction. In addition, moxibustion decreased the osteoclast number in RA rabbits. Real-time PCR revealed that moxibustion decreased the expression of RANKL mRNA while increased the expression of OPG mRNA, indicating a restoration of the balance between osteogenesis and osteoclastogenesis. Taken together, our results indicated that moxibustion had promising antiarthritic effects and could be an useful alternative method in RA therapeutics.
30478988 Long noncoding RNAs in autoimmune diseases. 2019 Feb With the completion of the human genome project and further development of high-throughput genomic technologies, interest in long noncoding RNAs (lncRNAs), which are defined as non-protein-coding RNAs at least 200 nucleotides in length, has strongly increased, and lncRNAs have become a major research direction. Increasing evidence demonstrates that lncRNAs are closely related to human growth and development and to disease occurrence via various mechanisms. lncRNAs also play crucial roles in the differentiation and activation of immune cells, and their relationships with human autoimmune diseases have received increasing attention. The development of biotechnology has led to the gradual discovery of many potential lncRNA functions. In this review, we discuss various lncRNAs that have been implicated in different human autoimmune diseases, focusing on their clinical applications as potential biomarkers and therapeutic targets in the pathologies of diverse human autoimmune diseases. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 468-475, 2019.
31662761 Demographic and Clinical Patterns of Rheumatoid Arthritis in an Emirati Cohort from United 2019 This retrospective cohort study aimed to assess the demographic and clinical characteristics of rheumatoid arthritis (RA) in Emirati patients attending Cleveland Clinic Abu Dhabi, a large tertiary center in the Middle East. In this study, 414 Emirati patients with RA were evaluated over a 3-year period from April 2015 to April 2018. All patients fulfilled the 2010 RA ACR/EULAR criteria and were assessed for demographic and clinical characteristics. The estimated RA prevalence rate in our population cohort was 2.72%. Females showed predominance (80%) with a higher body mass index (31.4 ± 6.61, P = 0.0001) compared to males (28.8 ± 6.03, P = 0.0001). The most frequent comorbidity observed was dyslipidemia (43.5%) followed by hypertension (37.9%), diabetes mellitus (34.5%), and gastroesophageal reflux disease (33.1%). Xerophthalmia was the most frequent extra-articular manifestation. Rheumatoid factor and anti-citrullinated peptide were detected in 63.3% and 41.5% patients, respectively, while both were present in 33.3% of patients. Methotrexate, adalimumab, and rituximab were the most frequently prescribed disease modifying agents. In this study, we describe disease features that are unique to United Arab Emirates (UAE) patients and demonstrate that RA has a significant disease burden. Our findings highlight the need for a RA national registry to improve the quality of care of these patients in UAE.
31007935 Inflammatory variant of pachydermoperiostosis responding to methotrexate: a report of two 2019 Apr Pachydermoperiostosis is a rare genetic disorder characterized by skin thickening, digital clubbing and periostitis. The pathogenesis is incompletely understood and there are no proven treatments for its manifestations. Although arthritis has been reported in 20-40% cases, most are non-inflammatory in nature and usually treated symptomatically with steroids or NSAIDs. We report two cases of pachydermoperiostosis with inflammatory variant of arthritis and raised inflammatory markers who were treated with tapering dose of prednisolone for 6 weeks and maintained on long-term low dose methotrexate like rheumatoid arthritis and followed for 2 years. In both cases, methotrexate was well tolerated and helped in maintaining symptomatic improvement and slowed the disease progression with significant steroid and NSAID sparing effect. We concluded that there exists an inflammatory subtype of disease where methotrexate can be beneficial.
31270087 Perplexing case of lung mass perfectly mimicking a malignancy. 2019 Jul 2 A 35-year-old man, a known asthmatic and with a history of smoking presented with a history of recurrent episodes of mild haemoptysis. On examination, there was decreased intensity of breath sounds on the right infraclavicular area. The chest X-ray and CT chest showed a mass in right upper lobe with nodules in the other lobe. The VAT showed large heavily vascularised mass with surface laden with multiple nodules. The wedge resection of the mass was taken and sent for histopathology examination. The biopsy result showed picture suggestive of connective tissue disease associated follicular bronchiolitis. The patient did not have any signs or symptoms of connective tissue disease. However he was positive for Rheumatoid factor, ANA, anti-RO, anti-CCP antibodies. He was started on steroids and azathioprine. After 6 months of treatment, the size of the mass and nodules reduced by 50% and ESR was reduced to 5 from 75.
30790155 PROMIS Fatigue short forms are reliable and valid in adults with rheumatoid arthritis. 2019 Feb 21 BACKGROUND: Fatigue is prevalent and impactful in rheumatoid arthritis (RA). There is no standardized measure for its assessment nor data concerning the performance of PROMIS-Fatigue short forms (SFs) in people with RA. We evaluated the construct validity of 4-, 7-, and 8-item PROMIS-Fatigue SFs in RA patients across the range of disease activity. METHODS: Adult RA patients were recruited from an online patient community and an observational cohort from three academic medical centers. Measures included PROMIS-Fatigue SFs, other PROMIS measures, and other patient reported outcomes including RAND-36 Vitality, Fatigue NRS, and patient global assessment of disease activity. Other measures from the observational cohort included 28-joint swollen and tender joints, physician global assessment, and the composite RA clinical disease activity index (CDAI). RESULTS: Two-hundred online participants and 348 participants from the observational cohort were included. PROMIS Fatigue SF scores spanned the measurement continuum and correlated highly with each other (r's ≥ 0.91) and other fatigue measures (r's ≥ 0.85). PROMIS-Fatigue SF scores were highly and inversely associated with Physical Function and Participation (r's - 0.77 to - 0.78), and moderately-highly and positively correlated with pain, sleep disturbance, anxiety, and depression (r's 0.60 to 0.75). PROMIS-Fatigue SF scores showed dose-response relationships across fatigue severity descriptors and CDAI categories. CONCLUSIONS: These results provide robust evidence supporting the construct validity of the 4, 7, and 8-item PROMIS-Fatigue SFs. They capture fatigue across the spectrum of RA disease activity in diverse groups of individuals and should be considered for use as patient-centered assessments of disease control and treatment efficacy.
31551776 TRPA1 Ion Channel Determines Beneficial and Detrimental Effects of GYY4137 in Murine Serum 2019 Modulation of nociception and inflammation by sulfide in rheumatoid arthritis and activation of transient receptor potential ankyrin 1 (TRPA1) ion channels by sulfide compounds are well documented. The present study aims to investigate TRPA1-mediated effects of sulfide donor GYY4137 in K/BxN serum-transfer arthritis, a rodent model of rheumatoid arthritis. TRPA1 and somatostatin sst4 receptor wild-type (WT) and knockout mice underwent K/BxN serum transfer and were treated daily with GYY4137. Functional and biochemical signs of inflammation were recorded, together with histological characterization. These included detection of hind paw mechanical hyperalgesia by dynamic plantar esthesiometry, hind paw volume by plethysmometry, and upside-down hanging time to failure. Hind paw erythema, edema, and passive movement range of tibiotarsal joints were scored. Somatostatin release from sensory nerve endings of TRPA1 wild-type and knockout mice in response to polysulfide was detected by radioimmunoassay. Polysulfide formation from GYY4137 was uncovered by cold cyanolysis. GYY4137 aggravated mechanical hyperalgesia in TRPA1 knockout mice but ameliorated it in wild-type ones. Arthritis score was lowered by GYY4137 in TRPA1 wild-type animals. Increased myeloperoxidase activity, plasma extravasation, and subcutaneous MIP-2 levels of hind paws were detected in TRPA1 knockout mice upon GYY4137 treatment. Genetic lack of sst4 receptors did not alter mechanical hyperalgesia, edema formation, hanging performance, arthritis score, plasma extravasation, or myeloperoxidase activity. TRPA1 WT animals exhibited smaller cartilage destruction upon GYY4137 administration. Sodium polysulfide caused TRPA1-dependent somatostatin release from murine nerve endings. Sulfide released from GYY4137 is readily converted into polysulfide by hypochlorite. Polysulfide potently activates human TRPA1 receptors expressed in Chinese hamster ovary (CHO) cells. According to our data, the protective effect of GYY4137 is mediated by TRPA1, while detrimental actions are independent of the ion channel in the K/BxN serum-transfer arthritis model in mice. At acidic pH in inflamed tissue sulfide is released from GYY4137 and reacts with neutrophil-derived hypochlorite. Resulting polysulfide might be responsible for TRPA1-mediated antinociceptive and anti-inflammatory as well as TRPA1-independent pro-inflammatory effects.
31863640 Quantitative analysis for modified Schall's classification by stimulation test with dynami 2020 Mar OBJECTIVES: To update Schall's classification for Sjögren's syndrome (SS) by the new quantitative stimulation test with dynamic salivary glands scintigraphy (qsDSGS) and to standardize quantitative salivary gland scintigraphy. METHODS: The histopathology, oral, ocular, serological examination and qsDSGS of 268 consecutive patients with suggestive SS were evaluated in this retrospective cohort study. The serological examination included 15 autoantibodies, antinuclear antibodies (ANA) and so on. The diagnostic thresholds of the functional parameters were set by the quantitative method, and the modified Schall's classification is well established and verified. RESULTS: Based on the quantitative analysis of qsDSGS, the peak uptake level (PUL) and stimulation excretion fraction (sEF) of each parotid gland were determined as the key imaging features, which had good diagnostic performance for SS. By the modified Schall's classification, all patients were classified into: Class 1 (normal; n = 44), Class 2 (mild to moderate involvement; n = 130), Class 3 (severe involvement; n = 56) and Class 4 (very severe involvement, non-function; n = 38). Using the threshold PUL ≤ 10 counts per sec/pixel as positivity, the modified Schall's classification could provide better diagnostic performance with 88.4% specificity, 71.3% sensitivity, 96.14% positive predictive value and 43.20% negative predictive value for SS (likelihood ratio 6.15). The trends of serologically positive frequencies against SSA/Ro, anti-SSB/La and ANA were significantly increased with the new classification. CONCLUSION: The modified Schall's classification by the new stimulation test with dynamic scintigraphy is eligible to standardize quantitative salivary gland scintigraphy for SS, and may be more convenient and suitable in daily practice for clinical research and management of SS.
31087133 [Biologics in the treatment of juvenile idiopathic arthritis : A comparison of mono- and c 2019 Sep In polyarticular juvenile idiopathic arthritis, methotrexate (MTX) is still used as first-line treatment. In case of insufficient response or intolerance, a number of biologics are now available. This faces physicians with challenging choices. Biologics are often combined with MTX, although in JIA there is little evidence and inconsistent results from various studies. In rheumatoid arthritis, combination therapy with tumor necrosis factor (TNF) inhibitors has been associated with higher efficacy. Tocilizumab appears to be highly effective as a monotherapy. MTX has a protective effect on the formation of anti-drug antibodies, which is particularly important for the use of anti-TNF antibodies. This could also be observed in children. For golimumab, combination with MTX is mandatory according to its approval, as is the cause for abatacept. With regard to tolerability, apart from the classic side effects of MTX, there are no other significant differences concerning the combination of MTX and biologics. In case of MTX intolerance, leflunomide may be considered as an (unapproved) alternative.
31326279 TREX1 variants in Sjogren's syndrome related lymphomagenesis. 2020 Aug Genetic variants of the three-prime repair exonuclease 1 (TREX1) -an exonuclease involved in DNA repair and degradation- have been previously found to increase susceptibility to Aicardi Goutieres syndrome, familial chilblain lupus and systemic lupus erythematosus. We aimed to explore whether TREX1 common variants could influence the risk of primary Sjogren's syndrome (SS) and SS-related lymphoma. Three single nucleotide polymorphisms (SNPs) of the TREX1 gene (rs11797, rs3135941 and rs3135945) were evaluated in 229 SS, 89 SS-lymphoma (70 SS-MALT and 19 SS non-MALT) and 240 healthy controls by PCR-based assays. In available 52 peripheral blood and 26 minor salivary gland tissues from our SS cohort, mRNA expression of type I interferon (IFN) related genes and TREX1 was determined by real-time PCR. Significantly decreased prevalence of rs11797 A minor allele was detected in SS patients complicated by non-MALT lymphoma compared to controls (ΟR [95% CI]: 0.4 [0.2-0.9], p-value: 0.02). SS patients carrying the rs11797 AA genotype had increased type I IFN related gene mRNA expression in minor salivary gland tissues. These data support genetically related dampened type I IFN production as an additional mechanism for SS-related lymphomagenesis.
31724352 [Observation on therapeutic effect of needle-knife for dry mouth and eyes symptoms of prim 2019 Nov 12 OBJECTIVE: To compare the clinical efficacy of needle-knife and hydroxychloroquine sulfate in the treatment of dry mouth and eyes symptoms of primary Sjögren's syndrome. METHODS: A total of 60 patients with primary Sjögren's syndrome were randomly divided into an observation group and a control group, 30 cases in each group. In the observation group, needle-knife was used in the range of 2 cm and 2-3 cm below the occipital protuberance, the left and right lateral bone edges of the C(2) spinous process, between and within the range of 1.5-3 cm beside the C(3) and C(4) spinous processes, points between the left and right mandibular angle and the mastoid, the treatment was given 1 time a week for 8 times. The hydroxychloroquine sulfate was applied 0.2 g each time, 2 times daily, 4 weeks as a course and a total of 2 courses in the control group. The changes of salivary flow rate, tear volume, serum immunoglobulin IgG, IgA, IgM contents and Chinese medicine symptom score were observed before and after treatment in the two groups, and the efficacy was evaluated. RESULTS: The total effective rate in the observation group was 86.7% (26/30), which was better than 70.0% (21/30) in the control group (P<0.05). The salivary flow rates, tear volume, serum IgG contents and Chinese medicine symptom scores in the two groups were significantly improved after treatment (all P<0.05), and the improvement degree in the observation group was better than the control group (all P<0.05). There was no significant difference in IgA and IgM between the two groups and before and after treatment (all P>0.05). CONCLUSION: Needle-knife is superior to hydroxychloroquine sulfate in improving dry mouth and eyes symptoms and reducing serum IgG content in patients with primary Sjögren's syndrome.
30632146 Contribution of FoxP3(+) Tfr cells to overall human blood CXCR5(+) T cells. 2019 Mar The identification that T follicular helper (Tfh) cells is critical for the emergence of germinal centre responses prompted the study of CXCR5-expressing CD4(+) T cell subsets in autoimmunity. However, circulating CXCR5-expressing T cells are heterogeneous by containing Forkhead box protein 3 (FoxP3)(+) T follicular regulatory (Tfr) cells in addition to bona fide Tfh cells. Such heterogeneity may hamper the analysis of the contribution of specific follicular T cell subsets for autoimmune pathogenesis. Therefore, separate assessment of Tfh and Tfr populations offer greater opportunities for stratification of autoimmune patients, such as Sjögren's syndrome patients.
31631466 Successful management of infliximab-induced generalized pustular psoriasis without therapy 2019 Nov While infliximab has been shown to be paradoxically associated with the development of pustular psoriasis in patients with rheumatoid arthritis, spondyloaripathies, juvenile idiopathic, and inflammatory bowel disease, there are few cases of pustular psoriasis induced by infliximab in patients with psoriasis. We here present a 55-year-old female patient with longstanding plaque psoriasis and psoriatic arthritis who developed generalized pustular psoriasis 1 month after the fifth infusion of infliximab. Given the lack of other side effects and the rapid initial response of the underlying psoriatic arthritis, we opted against discontinuing infliximab therapy, and the sixth infusion of infliximab was administered 10 days ahead of schedule. Topical corticosteroids were added for the management of pustular lesions on initial presentation. One week after the sixth infusion, the pustular psoriatic lesions almost completely disappeared. No recurrence of pustular psoriasis was observed during the 3-month follow-up. Our experience shows that pustular lesions associated with infliximab can be successfully managed with topical corticosteroids without discontinuing infliximab therapy or compromising therapeutic benefit seen upon the underlying condition.
31820172 Monoclonal Antibodies: Past, Present and Future. 2019 Monoclonal antibodies (mAbs) are immunoglobulins designed to target a specific epitope on an antigen. Immunoglobulins of identical amino-acid sequence were originally produced by hybridomas grown in culture and, subsequently, by recombinant DNA technology using mammalian cell expression systems. The antigen-binding region of the mAb is formed by the variable domains of the heavy and light chains and contains the complementarity-determining region that imparts the high specificity for the target antigen. The pharmacokinetics of mAbs involves target-mediated and non-target-related factors that influence their disposition.Preclinical safety evaluation of mAbs differs substantially from that of small molecular (chemical) entities. Immunogenicity of mAbs has implications for their pharmacokinetics and safety. Early studies of mAbs in humans require careful consideration of the most suitable study population, route/s of administration, starting dose, study design and the potential difference in pharmacokinetics in healthy subjects compared to patients expressing the target antigen.Of the ever-increasing diversity of therapeutic indications for mAbs, we have concentrated on two that have proved dramatically successful. The contribution that mAbs have made to the treatment of inflammatory conditions, in particular arthritides and inflammatory bowel disease, has been nothing short of revolutionary. Their benefit has also been striking in the treatment of solid tumours and, most recently, as immunotherapy for a wide variety of cancers. Finally, we speculate on the future with various new approaches to the development of therapeutic antibodies.
31612088 Hemophagocytic Syndrome-Associated Variant of Methotrexate-Associated Intravascular Large 2019 A 59-year-old man was treated for rheumatoid arthritis (RA) for 12 years with methotrexate (MTX) and prednisolone. After MTX-associated interstitial pneumonia developed, he was treated with cyclophosphamide and prednisolone for 7 months. Arthritis worsened, and tacrolimus was added to the treatment regimen. One month later, he had fever, loss of appetite, and dyspnea on exertion. Blood tests showed pancytopenia with large, atypical lymphocytes. Computed tomography showed mild splenomegaly. Bone marrow examination demonstrated CD20-positive, EBER-positive atypical lymphocytes, and hemophagocytosis. Random skin biopsy led to the diagnosis of intravascular large B-cell lymphoma (IVLBCL). The final diagnosis was a hemophagocytic syndrome-associated variant of IVLBCL. Complete remission was achieved after seven courses of R-CHOP. However, within a month, he complained of dizziness. Magnetic resonance imaging revealed focal infarctions in the cerebellum and around the left lateral ventricle. Central nervous system relapse was suspected. Although salvage chemotherapy (CHASER), whole brain irradiation, and intrathecal injection of cytarabine and prednisolone were temporarily effective, he died. Autopsy revealed infiltration of lymphoma cells in the brain and adrenal glands. To the best of our knowledge, this is the sixth case of IVLBCL and the first case of the hemophagocytic syndrome-associated variant of IVLBCL in RA patients in the literature.
31198584 Immunomodulatory nanodiamond aggregate-based platform for the treatment of rheumatoid arth 2019 Jun We previously demonstrated that octadecylamine-functionalized nanodiamond (ND-ODA) and dexamethasone (Dex)-adsorbed ND-ODA (ND-ODA-Dex) promoted anti-inflammatory and pro-regenerative behavior in human macrophages in vitro. In this study, we performed a pilot study to investigate if these immunomodulatory effects translate when used as a treatment for rheumatoid arthritis in mice. Following local injection in limbs of mice with collagen type II-induced arthritis, microcomputed tomography showed that mice treated with a low dose of ND-ODA and ND-ODA-Dex did not experience bone loss to the levels observed in non-treated arthritic controls. A low dose of ND-ODA and ND-ODA-Dex also reduced macrophage infiltration and expression of pro-inflammatory mediators iNOS and tumor necrosis factor-α compared to the arthritic control, while a high dose of ND-ODA increased expression of these markers. Overall, these results suggest that ND-ODA may be useful as an inherently immunomodulatory platform, and support the need for an in-depth study, especially with respect to the effects of dose.