Synergistic effect of anti-T cell receptor monoclonal antibody and 15-deoxyspergualin on cardiac xenograft survival in a mouse-to-rat model.
BACKGROUND
Successful xenograft transplantation faces several obstacles including the presence of xenoantibodies, natural killer cell- and macrophage-mediated rejection, and T lymphocyte activation.


METHODS
A mouse-to-rat cardiac xenograft model was used to examine the synergistic effect of anti-T cell receptor (TCR) monoclonal antibodies (mAb) and 15-deoxyspergualin (DSG) on graft survival.


RESULTS
Pretransplantation injections (days -5, -3, and -1) of anti-TCR mAb (500 microg/kg/day) combined with continuous i.p. infusion of DSG (5 mg/kg/day) from day -7 to 28 significantly prolonged graft survival compared to untreated controls (3.3+/-0.5 vs. 44.2+/-5.6 days, P<0.001). Postoperative splenectomy combined with discontinuation of all other treatment on day 28 enhanced graft survival in rats treated with anti-TCR mAb and DSG to 71.0+/-2.5 days. Histological examination of grafts showed characteristic signs of vascular rejection: interstitial edema and hemorrhage, and polymorphonuclear cell infiltration. Antimouse antibody titers in recipients were increased upon rejection in each group that received a xenograft. Flow cytometry analysis showed a markedly decreased T cell population and a relatively increased mature B cell population (IgM(bright)/IgD(dull)) in spleens of rats treated with anti-TCR mAb and DSG on day 28.


CONCLUSIONS
The mechanism of prolonged xenograft survival in this model may include inhibition of antibody production by arrest of B-cell maturation during development from IgM(dull)/IgD(bright) mature B cells to antibody producing cells, and inhibition of T cell activation. The rejection seen in our model may be caused by xenoreactive antibodies and may be associated with T cells, natural killer cells, and macrophages.
Haga
M
M
Department of Thoracic and Cardiovascular Surgery and Immunology, Niigata University School of Medicine, Japan.
Tsuchida
M
M
Hirahara
H
H
Watanabe
T
T
Hayashi
J I
JI
Watanabe
H
H
Matsumoto
Y
Y
Abo
T
T
Eguchi
S
S
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000276:immunology; D006085:Graft Survival; D006146:Guanidines / Q000627:therapeutic use*; D016027:Heart Transplantation; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013156:Splenectomy; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D006146:Guanidines; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007166:Immunosuppressive Agents; D011948:Receptors, Antigen, T-Cell; C037258:gusperimus