Table 4.
Overview of the above-mentioned studies investigating the relationship between BDNF and immunotherapies.
| Study | Participants | Parameters | Results |
|---|---|---|---|
| Aharoni et al. (117) | Animal study (mice) | Expression of TH2/3 cytokines and neurotrophic factors in glatiramer acetate specific T-cells | Increased levels of BDNF and IL-10 and transforming growth factor by astrocytes and microglia (among others) in glatiramer acetate treated mice |
| Aharoni et al. (116) | Animal study (mice) | Production of BDNF and other neurotrophins, as well as histopathology under glatiramer acetate treatment | Increased neurotrophins in treatment-naïve mice after EAE induction with lower concentrations over time compared to control mice Increased levels of BDNF, NT2 and NT3 in various brain regions under glatiramer acetate treatment with particularly high lesional concentration by migration of neuronal progenitors |
| Azoulay et al. (39) | 74 patients with RRMS (26 patients treated with IFN, 27 with glatiramer acetate, 21 without immunotherapy), 28 healthy controls | Measurement of BDNF (ELISA) | Lower BDNF levels in blood and CSF in patients with RRMS, increased in patients treated with glatiramer acetate Lower BDNF levels in patients with RRMS with acute relapse compared to stable patients with RRMS Only trend to higher BDNF levels in patients treated with IFN-β |
| Azoulay et al. (38) | 22 treatment-naïve patients with RR-MS, 27 IFN-β1a-treated RR-MS patients | BDNF in the supernatants of PBMCs (ELISA) | Higher BDNF levels in patients with RRMS treated with IFN-β1a, with upregulation by stimulation with anti-CD40 |
| Blanco et al. (110) | 19 treamtent-naïve patients with MS started on glatiramer acetate | Measurement of BDNF in unstimulated and stimulated (anti-CD3, anti-CD28) supernatants from PBMC by ELISA and intracellular cytokine production by flow Cytometry over 21 months | Decrease of BDNF production as well as INF-y producing total lymphocytes, CD4+ and CD8+ T cells, reduced percentage of IL2 producing CD4+ and CD8+ T-cells; increase of CD3+ and CD4+ and CD4 + CD45RA + T-cells after 6 months |
| Caggiula et al. (43) | 25 patients with RRMS, 14 patients with SPMS treated with IFN-β | Production of BDNF, NGF, GDNF, NT3, NT4 by PBMCs | Increasing BDNF levels in clinical stable patients with RRMS after 6 months of IFN-β treatment |
| Chen et al. (111) | 12 patients with MS treated with glatiramer acetate | BDNF production in different T-cell lines | Significant higher BDNF levels by resting T-cell lines Higher BDNF levels especially in glatiramer acetate stimulated T-cell lines |
| Ehling et al. (95) | 19 patients with RRMS (12 treated with glatiramer acetate, 7 treatment-naïve) | Serum BDNF over 24 months | No difference between patients treated with glatiramer acetate and treatment-naïve patients and no change of BDNF serum levels over time |
| Golan et al. (121) | 21 patients with MS | BDNF, GDNF, ß-NGF, NT-3, NT-4, FGF, EGF, VEGF (ELISA) before fingolimod treatment and after 6 and 12 months | Increaed BDNF levels after initiation of treatment with fingolimod |
| Kalinowska-Lyszczarz et al. (123) | 50 treatment naïve patients with RRMS, 39 healthy controls | BDNF levels in PBMCs lysates over one year of immunomodulation with IFN-β or glatiramer acetate (ELISA) | Lower BDNF levels in patients with MS compared to healthy controls No change of BDNF levels under immunotherapy without difference between treatment groups |
| Lee et al. (120), | Animal study (mice) | Effect of glatiramer acetate in BDNF knock-out mice | Limited clinical efficacy of glatiramer acetate after BDNF deletion in early disease phases |
| Liguori et al. (45) | 36 inactive patients with RRMS and 37 healthy controls | Effect of Val66Met polymorphism and BDNF levels on patients with RRMS over 24 months | Higher BDNF levels in patients with RRMS compared to healthy controls, regardless immunotherapy |
| Lindquist et al. (42) | 15 patients with RRMS, 1 patient with SPMS during acute relapse | Cytokine levels (TNF-a, iNOS, CNTF, BDNF) in PBMCs (flow-cytometric approach) | No effect of glucocorticoids on BDNF levels Increased BDNF levels in patients treated with IFN-β |
| Mehrpour et al. (51) | 82 patients with MS (15 treated with avonex, 13 with Rebif, 27 with Betaferon, 3 with Mitoxantrone, 2 with immunoglobulins, 22 without immunotherapies) | Serum BDNF levels (ELISA) | Higher BDNF levels in patients treated with IFN-β1b compared to patients treated with Mitoxantrone/patients without immunotherapies Negative correlation of BDNF with clinical impairment Patients with BDNF levels over 190 pg/ml indicated EDSS < 3 with 80% sensitivity |
| Petereit et al. (122) | 27 patients with RRMS, 10 healthy controls | BDNF blood level | Higher BDNF level patients with MS compared to healthy controls IFN-β and low dose immunoglobulin had no effect on BDNF levels, while high-dose immunoglobulin decreased BDNF levels |
| Sarchielli et al. (37) | 20 patients with RRMS (7 with acute relapse), 15 patients with SPMS, 20 healthy controls | Association of BDNF production by PBMCs unstimulated and stimulated with phytohemagglutinin, anti-OKT3 AB and MPB with clinicoradiological characteristics | Higher BDNF in supernatants of unstimulated and stimulated PBMCs in RRMS patients during and after relapse compared to stable phase Lower BDNF in unstimulated and stimulated PBMC supernatants of patients with SPMS compared to healthy controls, especially in patients with recent EDSS worsening (≥1 point in the last 6 months) |
| Sarchielli et al. (46) | 60 patients with RRMS (20 patients treated with IFN-β, 20 patients with glatiramer acetate, 20 patients with high dose immunoglobulins) | Cytokine and BDNF production by PBMCs over 2 years stimulated with Phytohemagglutinin, anti-OKT3 antibody, myelin basic protein | Increasing BDNF levels over 3 months in patients with MS treated with glatiramer acetate, afterwards levels remained stable but significantly higher compared to controls Decreased IFN-g, IL4, IL5, IL10 in patients treated with glatiramer acetate No effect of IFN-β1a/minimal decrease of BDNF levels under immunoglobulin treatment Increase of IL10 in patients treated with IFN-β1a |
| Shajarian et al. (15) | 45 patients with RRMS (32 treated with IFN-β, 13 treatment naïve), 45 healthy controls | Plasma BDNF and IL6 (ELISA) | Significant lower BDNF and higher IL6 in patients with MS compared to healthy controls No significant effect of IFN-β on BDNF plasma levels, but significant positive correlation of BDNF and IL-6 |
| Smith et al. (124) | Animal study (mice) | Association of brain volume in 7 T MRI with BDNF levels in blood, cerebrospinal fluid | Progressive brain volume loss despite clinical stability Less atrophy of cerebellum and striatum in mice treated early with fingolimod due to increased BDNF levels No influence of teriflunomide on atrophy rates |
| Vacaras et al. (50) | 19 patients with RRMS treated with glatiramer acetate, 11 patients with RRMS without immunotherapy, 12 healthy controls | BDNF in plasma, TrkB activation over 1 year | Reduced BDNF plasma level in patients with MS, no influence of glatiramer acetate after one year of sustained therapy |
| Vacaras et al. (125) | 22 patients with RRMS (11 treatment naïve, 11 treated with natalizumab), 9 patients with SPMS, 20 healthy controls | BDNF in plasma (ELISA) | Higher BDNF levels in patients with MS treated with natalizumab |
| Ziemssen et al. (118) | Patient with MS treated with glatiramer acetate, Healthy control | Glatiramer acetate specific T-cell lines, BDNF reverse-transcription PCR and two different BDNF measurement methods | BDNF production of all glatiramer acetate specific TH1, TH2 and TH0 after stimulation |
| Ziemssen et al. (112) | Patients with MS treated with glatiramer acetate, healthy controls | Glatiramer acetate specific T-cell lines, BDNF reverse-transcription PCR and two different BDNF measurement methods | BDNF production of all glatiramer acetate specific TH1, Th2 and Tho cell lines after stimulation |