Regulatory T cell frequency, but not plasma IL-33 levels, represents potential immunological biomarker to predict clinical response to intravenous immunoglobulin therapy.
Intravenous immunoglobulin (IVIG) is a polyspecific pooled immunoglobulin G preparation and one of the commonly used therapeutics for autoimmune diseases including those of neurological origin. A recent report in murine model proposed that IVIG expands regulatory T (Treg) cells via induction of interleukin 33 (IL-33). However, translational insight on these observations is lacking.



Ten newly diagnosed Guillain-Barré syndrome (GBS) patients were treated with IVIG at the rate of 0.4 g/kg for three to five consecutive days. Clinical evaluation for muscular weakness was performed by Medical Research Council (MRC) and modified Rankin scoring (MRS) system. Heparinized blood samples were collected before and 1, 2, and 4-5 weeks post-IVIG therapy. Peripheral blood mononuclear cells were stained for surface CD4 and intracellular Foxp3, IFN-γ, and tumor necrosis factor alpha (TNF-α) and were analyzed by flow cytometry. IL-33 and prostaglandin E2 in the plasma were measured by ELISA.



The fold changes in plasma IL-33 at week 1 showed no correlation with the MRC and MRS scores at weeks 1, 2, and ≥4 post-IVIG therapy. Clinical recovery following IVIG therapy appears to be associated with Tregcell response. Contrary to murine study, there was no association between the fold changes in IL-33 at week 1 and Tregcell frequency at weeks 1, 2, and ≥4 post-IVIG therapy. Tregcell-mediated clinical response to IVIG therapy in GBS patients was associated with reciprocal regulation of effector T cells-expressing TNF-α.



Tregcell expansion by IVIG in patients with autoimmune diseases lack correlation with IL-33. Tregcell frequency, but not plasma IL-33 levels, represents potential immunological biomarker to predict clinical response to IVIG therapy.
Institut National de la Santé et de la Recherche Médicale, Unité 1138, Paris, 75006, France.|Centre de Recherche des Cordeliers, Equipe- Immunopathologie et immuno-intervention thérapeutique, Paris, 75006, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR S 1138, Paris, 75006, France.|Université Paris Descartes, UMR S 1138, Paris, 75006, France.|Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA, 30329, USA.
Mohan S
MS
Maddur
Institut National de la Santé et de la Recherche Médicale, Unité 1138, Paris, 75006, France.|Centre de Recherche des Cordeliers, Equipe- Immunopathologie et immuno-intervention thérapeutique, Paris, 75006, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR S 1138, Paris, 75006, France.
Emmanuel
E
Stephen-Victor
Institut National de la Santé et de la Recherche Médicale, Unité 1138, Paris, 75006, France.|Centre de Recherche des Cordeliers, Equipe- Immunopathologie et immuno-intervention thérapeutique, Paris, 75006, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR S 1138, Paris, 75006, France.
Mrinmoy
M
Das
Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, 560012, India.
Praveen
P
Prakhar
Institut National de la Santé et de la Recherche Médicale, Unité 1138, Paris, 75006, France.|Centre de Recherche des Cordeliers, Equipe- Immunopathologie et immuno-intervention thérapeutique, Paris, 75006, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR S 1138, Paris, 75006, France.|Université Paris Descartes, UMR S 1138, Paris, 75006, France.
Varun K
VK
Sharma
Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, 560012, India.
Vikas
V
Singh
Sorbonne Universités, UPMC Univ Paris 06, UMR S 1138, Paris, 75006, France.
Magalie
M
Rabin
Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, 560012, India.
Jamma
J
Trinath
Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, 560012, India.
Kithiganahalli N
KN
Balaji
Réanimation Neurologique, Neurologie 1, Hôpital de la Pitié-Salpêtrière, Paris, 75651, France.
Francis
F
Bolgert
Centre de Référence 'Neuropathies Périphériques Rares' et Service de Neurologie, Hôpital Universitaire Limoges, Limoges, 87042, France.
Jean-Michel
JM
Vallat
Centre de Référence 'Neuropathies Périphériques Rares' et Service de Neurologie, Hôpital Universitaire Limoges, Limoges, 87042, France.
Laurent
L
Magy
Institut National de la Santé et de la Recherche Médicale, Unité 1138, Paris, 75006, France. srini.kaveri@crc.jussieu.fr.|Centre de Recherche des Cordeliers, Equipe- Immunopathologie et immuno-intervention thérapeutique, Paris, 75006, France. srini.kaveri@crc.jussieu.fr.|Sorbonne Universités, UPMC Univ Paris 06, UMR S 1138, Paris, 75006, France. srini.kaveri@crc.jussieu.fr.|Université Paris Descartes, UMR S 1138, Paris, 75006, France. srini.kaveri@crc.jussieu.fr.
Srini V
SV
Kaveri
Institut National de la Santé et de la Recherche Médicale, Unité 1138, Paris, 75006, France. jagadeesh.bayry@crc.jussieu.fr.|Centre de Recherche des Cordeliers, Equipe- Immunopathologie et immuno-intervention thérapeutique, Paris, 75006, France. jagadeesh.bayry@crc.jussieu.fr.|Sorbonne Universités, UPMC Univ Paris 06, UMR S 1138, Paris, 75006, France. jagadeesh.bayry@crc.jussieu.fr.|Université Paris Descartes, UMR S 1138, Paris, 75006, France. jagadeesh.bayry@crc.jussieu.fr.
Jagadeesh
J
Bayry
D000368:Aged; D000369:Aged, 80 and over; D015232:Dinoprostone / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D020275:Guillain-Barre Syndrome / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use*; D007155:Immunologic Factors / Q000627:therapeutic use*; D000067596:Interleukin-33 / Q000097:blood*; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D011237:Predictive Value of Tests; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric; D050378:T-Lymphocytes, Regulatory / Q000473:pathology*
D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D000067596:Interleukin-33; D015232:Dinoprostone
Clinical response; Guillain-Barré syndrome; IL-33; IVIG; Regulatory T cells; TNF-α; Treg cells