Engineering Immune Tolerance with Targeted Immunotherapies

Many current autoimmune disease therapies act through nonspecific suppression of the immune response, resulting in global immunosuppression and deleterious off-target effects. Antigen-specific immunotherapies that target and suppress only offending autoreactive immune cells to restore autoantigenic tolerance would address a pressing need for safer and more effective therapies, yet remain elusive. Endogenous mechanisms for maintaining immunological tolerance and homeostasis suggest however that restoration of immune tolerance is plausible. For example, mucosal tolerance against ingested antigens is maintained through mechanisms of oral tolerance, where antigens are taken up, processed, and presented in gut-associated lymphoid tissues (GALT) in a highly tolerogenic context. Peripheral tolerance is maintained primarily through a state of antigen unresponsiveness called anergy which occurs when lymphocytes (B or T cells) mount an initial response to primary antigenic signal but do not receive sufficient secondary costimulatory signals to sustain activation. B cells in particular, which contribute to autoimmune pathogenesis through antigen presentation and effector functions, have potential for direct antigen-specific targeting through the B cell receptor (BCR) and provide a promising target for tolerogenic immunotherapies. Multivalent nanomaterials (such as soluble antigen arrays, or cSAgAs) that present multiple copies of covalently-conjugated autoantigen can be tailored to induce anergy in autoimmune B cells through high avidity binding of the BCR in the absence of costimulatory signals to modulate BCR signaling. Design and development of effective cell-targeted antigen-specific immunotherapies should take into account appropriate physicochemical properties of delivered antigen in light of known molecular, cellular, and transport mechanisms for inducing peripheral tolerance. This project seeks to build upon endogenous mechanisms of tolerance to design targeted antigen-specific immunotherapies to treat autoimmune diseases.

Proposed mechanism for inducing B cell anergy with multivalent autoantigen arrays. (Adapted from Hartwell et al. Journal of Autoimmunity, 2018.)

Supporting publications:

Hartwell BL, Pickens CJ, Leon M, Northrup L, Christopher MA, Griffin JD, Martinez-Becerra F, Berkland C. “Soluble antigen arrays disarm antigen-specific B cells to promote lasting immune tolerance in EAE.” J Autoimmunity. 2018; 93(9):76-88. DOI: 10.1016/j.jaut.2018.06.006

Hartwell BL, Pickens CJ, Leon M, Berkland C. “Multivalent antigen arrays exhibit high avidity binding and modulation of B cell receptor-mediated signaling to drive efficacy against EAE.” Biomacromolecules. 2017; 18(6):1893-1907. DOI: 10.1021/acs.biomac.7b00335

Hartwell BL, Martinez-Becerra F, Chen J, Shinogle H, Sarnowski M, Moore D, Berkland C. “Antigen-specific binding of multivalent soluble antigen arrays induces receptor clustering and impedes B cell receptor mediated signaling.” Biomacromolecules. 2016; 17(3): 710-22. DOI: 10.1021/acs.biomac.5b01097

Hartwell BL, Smalter Hall A, Swafford D, Sullivan BP, Garza A, Sestak JO, Northrup L, Berkland C. “Molecular dynamics of multivalent soluble antigen arrays support two-signal codelivery mechanism in treatment of experimental autoimmune encephalomyelitis.” Molecular Pharmaceutics. 2016; 13(2): 330-43. DOI: 10.1021/acs.molpharmaceut.5b00825

Hartwell BL, Antunez L, Sullivan BP, Thati S, Sestak JO, Berkland C. “Multivalent nanomaterials: learning from vaccines and progressing to antigen-specific immunotherapies.” Journal of Pharmaceutical Science. 2015; 104(2): 346-61. Epub 2014. DOI: 10.1002/jps.24273

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