Short-term T cell receptor directed immunotherapy induces organ specific peripheral tolerance in a strongly incompatible rat model.
We analysed the effect of selective alpha/beta-T cell elimination on allograft survival in a strongly histoincompatible DA-->LEWIS rat model by treatment of recipients with the mouse monoclonal antibody R73 two times before and seven times after transplantation. R73 induced virtually indefinite cardiac allograft survival in 44% of six-week-old LEWIS recipients, whereas donor-type skin allografts were rejected within 11 days. The remaining 56% of animals presented a mean cardiac survival time of 41 +/- 13 days. Graft prolongation was age dependent since in ten-week-old animals the survival time was only of 19 +/- 5 days (untreated controls: 7 +/- 1 days). R73 induced a rapid decrease of R73-positive T cells in the peripheral blood from 70% before treatment to 2%. From the fifth day of treatment a gradual T cell recovery was registered. The T cell marker CD5 decreased from 72% to 17% but recovered already from the second day of treatment. Determination of alpha/beta-TCR, CD3 and CD5 density on T cells during R73 therapy showed that the initial T cell decrease was due to T cell elimination, whereas modulation of alpha/beta-TCR was predominant during the following days. Anti-R73 antibodies appeared regularly during the first week of treatment and blocked R73 activity, indicating their anti-idiotypic nature. The present findings show that short-term R73 therapy is able to induce long-lasting allograft survival. This experimental model can be used to study the basis of peripheral organ specific T cell tolerance.
Dufter
C
C
Department of Transplantation Immunology, University Hospital Heidelberg, Germany.
Post
S
S
Thies
J
J
Otto
G
G
Gaweco
A
A
Meuer
S
S
Terness
P
P
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology; D007108:Immune Tolerance; D051379:Mice; D009928:Organ Specificity; D051381:Rats; D011917:Rats, Inbred Lew; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis / Q000276:immunology / Q000502:physiology*; D016038:Skin Transplantation; D014181:Transplantation Immunology; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D016693:Receptors, Antigen, T-Cell, alpha-beta