TACI-Fc gene therapy improves autoimmune sialadenitis but not salivary gland function in non-obese diabetic mice.
OBJECTIVE
Patients with Sjögren's syndrome (SS) show aberrant expression of the B cell-related mediators, B cell-activating factor (BAFF), and a proliferation-inducing ligand (APRIL) in serum and salivary glands (SGs). We studied the biological effect of neutralizing these cytokines by local gene transfer of the common receptor transmembrane activator and CAML interactor (TACI) in an animal model of SS.


METHODS
A recombinant serotype 2 adeno-associated virus (rAAV2) encoding TACI-Fc was constructed, and its efficacy was tested in the SGs of non-obese diabetic mice. Ten weeks later, SG inflammation was evaluated and serum and SG tissue were analyzed for inflammatory markers including immunoglobulins (Ig) and cytokines.


RESULTS
AAV2-TACI-Fc gene therapy significantly reduced the number of inflammatory foci in the SG, owing to a decrease in IgD(+) cells and CD138(+) cells. Moreover, IgG and IgM levels, but not IgA levels, were reduced in the SG. Overall expression of mainly proinflammatory cytokines tended to be lower in AAV2-TACI-Fc-treated mice. Salivary flow was unaffected.


CONCLUSIONS
Although local expression of soluble TACI-Fc reduced inflammation and immunoglobulin levels in the SG, further research will have to prove whether dual blockade of APRIL and BAFF by TACI-Fc can provide a satisfying treatment for the clinical symptoms of patients.
Division of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. j.l.vosters@amc.uva.nl
J L
JL
Vosters
N
N
Roescher
G G
GG
Illei
J A
JA
Chiorini
P P
PP
Tak
D000818:Animals; D053264:B-Cell Activating Factor / Q000037:antagonists & inhibitors; D001402:B-Lymphocytes / Q000473:pathology; D016207:Cytokines / Q000032:analysis; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D007070:Immunoglobulin A / Q000032:analysis; D007072:Immunoglobulin D / Q000032:analysis; D007074:Immunoglobulin G / Q000032:analysis; D007075:Immunoglobulin M / Q000032:analysis; D018836:Inflammation Mediators / Q000032:analysis; D008024:Ligands; D051379:Mice; D016688:Mice, Inbred NOD; D010950:Plasma Cells / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000627:therapeutic use*; D012463:Saliva / Q000737:chemistry / Q000378:metabolism; D012636:Secretory Rate / Q000502:physiology; D012793:Sialadenitis / Q000276:immunology / Q000473:pathology; D012859:Sjogren's Syndrome / Q000097:blood / Q000473:pathology / Q000628:therapy*; D013363:Submandibular Gland / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D053668:Syndecan-1 / Q000032:analysis; D014161:Transduction, Genetic; D053303:Transmembrane Activator and CAML Interactor Protein / Q000235:genetics / Q000627:therapeutic use*; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000037:antagonists & inhibitors
D053264:B-Cell Activating Factor; D016207:Cytokines; D007070:Immunoglobulin A; D007072:Immunoglobulin D; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D018836:Inflammation Mediators; D008024:Ligands; D011993:Recombinant Fusion Proteins; C508242:Sdc1 protein, mouse; D053668:Syndecan-1; C486361:Tnfrsf13b protein, mouse; C491959:Tnfsf13 protein, mouse; C505720:Tnfsf13b protein, mouse; D053303:Transmembrane Activator and CAML Interactor Protein; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; C524618:TACI receptor-IgG Fc fragment fusion protein