B-cell delivered gene therapy for tolerance induction: role of autoantigen-specific B cells.
Antigen-specific tolerance induction using autologous B-cell gene therapy is a potential treatment to eliminate undesirable immune responses. For example, we have shown that experimental autoimmune encephalomyelitis (EAE) and type 1 diabetes in NOD mice can be ameliorated using antigen-Ig fusion protein transduced B cells. However, it is well established that auto-reactive antigen-specific B cells are activated in many autoimmune diseases and can contribute to pathogenesis. While syngeneic B cells from immunized or autoimmune mice can serve as tolerogenic antigen-presenting cells (APC), this observation begs the question of whether the antigen-specific B cells per se can be transduced as tolerogenic APC. To test this, we employed two model systems employing B cell receptor (BCR) transgenic or wild type (wt) mice as B-cell donors. While adoptively transferred MOG-Ig transduced wt C57Bl/6 B cells were highly tolerogenic and ameliorated EAE, MOG-Ig transduced anti-MOG B cells from BCR transgenic mice were not. This phenomenon was reproduced in the NOD diabetes model in which pro-insulin-Ig transduced polyclonal wt NOD B cells were protective, whereas similarly transduced anti-insulin BCR B cells were not. Since the frequency of antigen-specific B cells in an immunized animal is quite low, we wished to determine the threshold numbers of BCR transgenic B cells that could be present in an effective transduced population. Therefore, we "spiked" polyclonal wt C57Bl/6 B cells with different numbers of anti-MOG BCR transgenic B cells. In the EAE model, we found protection when BCR B cells were present at 1%, but they prevented tolerance induction at 10%. Antigen-specific B cells expressed normal levels of co-stimulatory molecules and were tolerogenic when transduced with an irrelevant antigen (OVA). Thus, the presence of a BCR specific for the target autoantigen may interfere with the tolerogenic process to that antigen, but BCR-specific B cells are not intrinsically defective as tolerogenic APC. Taken together, these data suggest that antigen-specific tolerance induction can be achieved in the presence of a limited number of antigen-specific B cells, but higher numbers of pathogenic B cells may mask this induction. This observation should guide future development of therapies using autologous B cells to treat patients with autoimmune diseases.
Zhang
Ai-Hong
AH
Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Li
Xin
X
Onabajo
Olusegun O
OO
Su
Yan
Y
Skupsky
Jonathan
J
Thomas
James W
JW
Scott
David W
DW
D019264:Adoptive Transfer; D000818:Animals; D001324:Autoantigens; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002452:Cell Count; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D015316:Genetic Therapy; D007108:Immune Tolerance; D007136:Immunoglobulins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007328:Insulin / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D011947:Receptors, Antigen, B-Cell / Q000235:genetics
D001324:Autoantigens; D007136:Immunoglobulins; D007328:Insulin; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D011947:Receptors, Antigen, B-Cell