Characteristics of the Induction Phase of Antithymocyte-Globulin-Induced Heart Allograft Tolerance in the Rat

Abstract

Transplantation tolerance was induced in 50% of Wky rats treated with antithymocyte globulin (ATG) 2 days prior to transplantation of a PVG/c heart. The induction period immediately following ATG treatment and transplantation was characterized by instability, with 50% of the allografts being lost in rejection within 30 days after transplantation. Second syngeneic transplantation to ATG-treated recipients 5 days after the first transplantation facilitated tolerance induction and permanent acceptance of both transplants. Thirty days after ATG treatment and the primary transplantation, 50% of second syngeneic allografts were accepted. During the early period after transplantation a continuous antigen presence together with ATG was necessary. Graft removal and absence of the transplant for 3 days, close to ATG administration, resulted in rejection of a second PVG/c transplant. Furthermore, the induction phase could easily be manipulated by the addition of sensitized or tolerized spleen cells to the recipient, causing allograft rejection or tolerance, respectively. Sixty days after ATG treatment and transplantation, a longer period between graft removal and retransplantation was required to break tolerance. Injection of sensitized spleen cells at this time did not affect graft survival, indicating an increased stability of the unresponsive state 60 days after ATG treatment and transplantation.

Alteration in T Cell Subset Phenotypes as Cell Markers for Rejection or Long-Term Allograft Acceptance in Allografted Rats Treated with Antithymocyte Globulin

“…We have used our own rabbit antirat thy mocyte globulin in studies of rat heart allograft tolerance induction. A single dose of ATG given prior to transplan tation resulted in more than 50% long-term surviving (LTS) grafts [4], The induction phase in the development of LTS grafts after ATG treatment is unstable and can eas ily be manipulated [6]. In the long run, this allograft toler ance is stable and detectable by cell-mediated lympholysis (CML) unresponsiveness [7] and acceptance of second syngeneic grafts [4],…”

Antithymocyte Globulin and Cyclosporin A are Synergistic in an Experimental Transplantation Tolerance Model in the Rat

“…shown to be of importance to allow permanent graft acceptance during the early induction phase [33]. In order to trigger rejection, the stimulus by Linomide® of these immunocompetent cells during the first 10 postoperative days was insufficient, and to be effective the drug had to be given for up to 21 days, when the number of immunocompetent cells had increased sufficiently after ATG treatment [14].…”

“…In several reports, an active suppressor-cell mechanism has been suggested [16,17]. The process of tolerance induction after ATG treatment has also been shown to be dose dependent [15] and to require continuous antigen presence [33], especially close to transplantation. The ATG dose also influences the level of T-cell depletion in peripheral blood [14].…”

“…Giving ATG for a prolonged period during the sensitive induction period following transplantation could theoretically deplete 'useful' T cells with suppressor capability, resulting in an abrogated tolerance induction. As ATG has also been shown to be less effective when given after transplantation [33], it therefore seems logical to recommend that a short course of ATG be given prior to transplantation.…”

Tolerance or Rejection: A Delicate Balance as Judged by Exposure of Heart‐Transplanted Rats to the Immunomodulator Linomide®

“…T-cell stimulation and prevention of apoptosis of active clones), it is reasonable to suppose that the quality of tolerance and the tolerance induction mechanism will differ from one situation to another, in variation of rat strain combinations and induction modalities. In one system, namely that of ATG-induced tolerance, the cause of tolerance may well be suppressor cells [40]. However, this tolerance induction is severely hampered by Linomide Ò [11].…”