Mechanisms of immunotherapeutic intervention by anti-CD154 (CD40L) antibody in high-risk corneal transplantation.
This study aimed to determine the effects of anti-CD154 on T cell cytokine profiles and ocular chemokine gene expression after high-risk corneal transplantation and to specifically determine if CD154 blockade is associated with a switch from a Th1 to a Th2 alloimmune response. Mice were used as recipients of syngeneic or multiple minor H or MHC antigen-mismatched corneal grafts. Recipient beds were neovascularized (high-risk). Hosts were randomized to receive either anti-CD154 antibody or control immunoglobulin (Ig) perioperatively. Two weeks after corneal transplantation, allospecific delayed-type hypersensitivity (DTH) was evaluated. Frequencies of interferon-gamma (IFN-gamma)-, interleukin-2 (IL-2)-, IL-4-, and IL-5-secreting T cells in the hosts were measured by enzyme-linked immunospot (ELISPOT) assay. Ocular chemokine gene expression in anti-CD154-treated and control hamster Ig-treated groups was determined using a multiprobe ribonuclease protection assay (RPA). Leukocyte infiltration of corneal grafts was evaluated microscopically. Anti-CD154-treated mice did not exhibit allospecific DTH. The frequencies of Th1 cytokine-producing but not Th2 cytokine-producing T cells were significantly reduced in anti-CD154-treated hosts. Postoperative mRNA levels of RANTES and macrophage inflammatory protein-1beta (MIP-1beta) in anti-CD154-treated eyes were substantially suppressed compared with hamster Ig-treated controls. Leukocyte infiltration was profoundly suppressed in grafts of anti-CD154-treated hosts. These data demonstrate that blockade of the CD40-CD154 costimulatory pathway after corneal transplantation inhibits Th1-mediated responses but does not induce a switch to a Th2-specific response. In addition, anti-CD154 therapy suppresses ocular chemokine gene expression and leukocytic infiltration into allografts.
Qian
Ying
Y
Department of Ophthalmology, The Schepens Eye Research Institute, Harvard Medical School, 20 Staniford Street, Boston, MA 02114, USA.
Hamrah
Pedram
P
Boisgerault
Florence
F
Yamagami
Satoru
S
Vora
Sudhir
S
Benichou
Gilles
G
Dana
M Reza
MR
D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D023201:CD40 Ligand / Q000276:immunology*; D003315:Cornea / Q000098:blood supply; D016039:Corneal Transplantation / Q000276:immunology*; D006801:Humans; D006968:Hypersensitivity, Delayed; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D009389:Neovascularization, Pathologic / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
D000906:Antibodies; D007166:Immunosuppressive Agents; D023201:CD40 Ligand