Depletion of LAG-3 positive cells in cardiac allograft reveals their role in rejection and tolerance.
BACKGROUND
Lymphocyte-activated gene-3 (LAG-3, CD223) is upregulated during the early stages of T-cell activation and could be the target of cytotoxic antibodies for induction therapy in transplantation.


METHODS
Fully vascularized heterotopic allogeneic heart transplantation was performed in rats across a full major histocompatibility complex-mismatch barrier (LEW.1W into LEW.1A). Recipients received two injections (day 0 and 3) of cytotoxic antibodies directed to the extra-loop of LAG-3 immunoglobulin (Ig)-like N-terminal domain or control antibodies.


RESULTS
LAG-3 mRNA transcripts accumulated in cardiac allografts undergoing rejection, but not in peripheral lymphoid organs. Administration of anti-LAG-3 antibodies on the day of transplantation did not modify alloreactivity of T lymphocytes from the spleen and did not change the alloantibody response. However, it inhibited graft infiltration by effector mononuclear cells, reduced intragraft levels of interferon-gamma mRNA and prolonged allograft survival from 6 days in controls to a median of 27 days. Anti-LAG-3 antibodies were also active in prolonging survival when administered in a delayed manner, after rejection onset. LAG-3 being also expressed by activated regulatory T (Treg) cells, we tested the effect of anti-LAG-3 antibodies on graft acceptance after donor blood transfusions, a Treg-dependent tolerance induction model. We found that tolerance induction was prevented by anti-LAG-3 antibodies.


CONCLUSIONS
Targeting LAG-3-positive cells with cytotoxic antibodies is immunosuppressive in transplantation by depleting effectors T cells and therefore may represent a treatment for rejection episodes focused only on pathogenic cells. However, it might not be compatible with tolerance-induction strategies.
Haudebourg
Thomas
T
University of Nantes School of Medicine, Nantes, France.
Dugast
Anne-Sophie
AS
Coulon
Flora
F
Usal
Claire
C
Triebel
Frederic
F
Vanhove
Bernard
B
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000633:toxicity; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D001803:Blood Transfusion; D005786:Gene Expression Regulation; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival; D016027:Heart Transplantation; D006433:Hemocyanins / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D007114:Immunization; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D008297:Male; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D013154:Spleen / Q000187:drug effects; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology; D000093322:Lymphocyte Activation Gene 3 Protein
D000906:Antibodies; D015703:Antigens, CD; D012333:RNA, Messenger; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin; D000093322:Lymphocyte Activation Gene 3 Protein