Neutralizing and Targeting Properties of a New Set of α4β7-Specific Antibodies Are Influenced by Their Isotype.
The homing of lymphocytes to the mucosa is mainly controlled by α4β7 integrin, and it is amplified during gut chronic inflammation, as occurs with HIV and/or inflammatory bowel diseases. We designed and applied an improved immunization strategy based on an innovative selection process to isolate new α4β7 lymphocyte-specific monoclonal antibodies that are able to prevent their migration into inflamed gut tissues and/or to counteract HIV infection in vitro. First, 5 monoclonal antibodies (1 IgA, 1 IgM, and 4 IgGs) were selected based on their capacity to recognize α4 or β7 homodimers and α4β7 heterodimers in transfected human cells. Their ability to block gp120/α4β7 or MAdCAM-1/α4β7 interactions was then measured in vitro with human T and B lymphocytes. In vitro, the anti-α4β7 IgA isotype was found to have the highest affinity for the α4β7 heterodimer, and it significantly reduced HIV replication in retinoic acid-treated α4β7 CD4 human T cells. This α4β7-specific IgA also displayed a high avidity for human and mouse α4β7 lymphocytes in both mouse and human inflammatory colitis tissues. These new antibodies, and in particular those with mucosa-targeting isotypes such as IgA, could therefore be potential novel therapeutic tools for treating HIV and inflammatory bowel disease.
*GIMAP/EA3064, Université de Lyon, Saint-Etienne, France; †NIH/NIAID Laboratory of Immunoregulation, Bethesda, MD; ‡Institut de Biologie et Chimie des Protéines, FRE3310/CNRS, Universités de Lyon, Lyon, France; and §Dendritics SA, Lyon, France.
Alexandre
A
Girard
Katija
K
Jelicic
Don
D
Van Ryk
Nicolas
N
Rochereau
Claudia
C
Cicala
James
J
Arthos
Blandine
B
Noailly
Christian
C
Genin
Bernard
B
Verrier
Stephanie
S
Laurant
Diane
D
Razanajaoana-Doll
Jean-Jacques
JJ
Pin
Stéphane
S
Paul
D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D006678:HIV / Q000502:physiology; D006801:Humans; D007132:Immunoglobulin Isotypes / Q000276:immunology*; D007155:Immunologic Factors / Q000494:pharmacology; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000276:immunology*; D008807:Mice, Inbred BALB C; D013601:T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D014779:Virus Replication
D019380:Anti-HIV Agents; D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D007132:Immunoglobulin Isotypes; D007155:Immunologic Factors; D016023:Integrins; C071777:integrin alpha4beta7