title: Protein kinase C independent restoration of specific immune responsiveness in common variable immunodeficiency.
abstract: 7,8-Disubstituted guanine ribonucleosides represent a class of B lymphocyte agonists that utilize a protein kinase C-independent signaling pathway. These compounds provide an alternate T helper signal for B cells and enhance antigen-specific humoral responses in the murine model and in an IL-2-dependent human model in vitro. They effectively restore high level immune responses in a variety of murine models of immunodeficiency both in vivo and in vitro. In this study we examined the potential of these compounds to improve antibody responses generated by cultured cells from patients with common variable immunodeficiency (CVI). The inability to mount normal humoral responses to antigen was confirmed in nine patients with diagnosed CVI (CVI: 37 +/- 16, normal 653 +/- 116 plaque-forming cells (PFC)/culture; P less than 0.001). In cultured lymphocytes from eight of the nine patients studied, a normal level or greater responses to nominal antigen could be elicited by antigen in the presence of the immunostimulatory nucleoside 7-methyl-8-oxoguanosine (7m8oGuo). The average response to antigen increased from 37 +/- 16 without nucleoside to 1733 +/- 488 PFC/culture in its presence (P less than 0.002). Restoration of specific immune responses was an antigen-dependent and nucleoside dose-dependent event. Signaling by 7m8oGuo rendered the response to antigen protein kinase C independent in cultures of cells from normal donors as well as from CVI patients. These data substantiate (i) that a non-C-kinase signaling pathway for antigen-dependent differentiation exists, (ii) that this pathway can function normally in B cells from patients with CVI when triggered appropriately, and (iii) that 7,8-disubstituted guanine ribonucleosides can convert a C-kinase-dependent signaling event to a C-kinase-independent signaling event. Substituted guanine ribonucleosides may have potential as immunotherapeutic agents for patients with CVI.
authors.affiliation: Department of Immunology, Research Institute of Scripps Clinic, La Jolla, California 92037.
authors.forename: M G
authors.initials: MG
authors.lastname: Goodman
authors.forename: S
authors.initials: S
authors.lastname: Gupta
authors.forename: M E
authors.initials: ME
authors.lastname: Rosenthale
authors.forename: R J
authors.initials: RJ
authors.lastname: Capetola
authors.forename: S C
authors.initials: SC
authors.lastname: Bell
authors.forename: W O
authors.initials: WO
authors.lastname: Weigle
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000328:Adult; D000470:Alkaloids / Q000494:pharmacology; D000917:Antibody Formation / Q000187:drug effects; D015703:Antigens, CD / Q000032:analysis; D002455:Cell Division / Q000187:drug effects; D003208:Concanavalin A / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006151:Guanosine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D007070:Immunoglobulin A / Q000032:analysis; D007074:Immunoglobulin G / Q000032:analysis; D007075:Immunoglobulin M / Q000032:analysis; D007153:Immunologic Deficiency Syndromes / Q000276:immunology*; D016130:Immunophenotyping; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D008214:Lymphocytes / Q000276:immunology; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000494:pharmacology; D011043:Pokeweed Mitogens / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology*; D047428:Protein Kinase Inhibitors; D015398:Signal Transduction / Q000502:physiology; D013110:Sphingosine / Q000494:pharmacology; D019311:Staurosporine
chemical_list: D000470:Alkaloids; D015703:Antigens, CD; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007546:Isoquinolines; D010879:Piperazines; D011043:Pokeweed Mitogens; D047428:Protein Kinase Inhibitors; D003208:Concanavalin A; D006151:Guanosine; C050068:7-methyl-8-oxoguanosine; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C068562:loxoribine; D011493:Protein Kinase C; D019311:Staurosporine; D013110:Sphingosine