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Treatment with CTLA4-Ig inhibits rejection of liver allografts from Flt3-ligand–treated donors
Treatment With CTLA4-Ig Inhibits Rejection of Liver Allografts From Flt3-Ligand–Treated Donors F. Fu, W. Li, L. Lu, J.J. Fung, A.W. Thomson, and S. Qian
B
10 (H-2b) mouse livers are accepted spontaneously in C3H (H-2k) recipients without the requirement for immunosuppressive therapy (median survival time [MST] .100 days).1 However, livers from B10 donors pretreated with Flt3 ligand (FL), a recently cloned hematopoietic cytokine that dramatically increases the number of functional dendritic cells (DC) in lymphoid and nonlymphoid tissues, including the liver, are rejected acutely in normal C3H recipients (MST 5 days).2 This switch from tolerance to rejection is correlated with dramatic increases in DC with high cell surface expression of MHC class II and costimulatory molecules (CD40, CD80 [B7-1], and CD86 [B7-2]) isolated from the donor organ at the time of transplant.2,3 The objective of this study was to determine the role of B7/CD28 ligation in the conversion of liver transplant tolerance to rejection by donor treatment with FL using CTLA4-Ig, an immunoglobulin fusion protein that specifically blocks the ligands for CD28.4 This may lead to better understanding of the regulatory role of liver DC in transplant tolerance. MATERIALS AND METHODS C3H recipients were given CTLA4-Ig (Bristol-Myers Squibb, Princeton, NJ), 200 mg, as one intraperitoneal (IP) dose immediately after transplantation. Controls received no treatment. Livers were transplanted orthotopically from either normal B10 donors or B10 mice pretreated with FL (Immunex, Seattle, Wash; 10 mg/d IP for 10 consecutive days before transplantation).
other species are not fully understood. We have recently demonstrated that liver allograft acceptance is associated with high levels of CTL apoptotic death within the graftinfiltrating cell population.5 There is evidence that passenger leukocytes and their progenitors in liver grafts, including DC, may play a role in affecting the outcome of liver transplantation. Thus, normal liver-derived DC progenitors have the capacity to prolong graft survival.6 However, liver allografts containing high numbers of mature DC expressing high MHC class II and costimulatory molecules (CD40, CD80 [B7-1], and CD86 [B7-2]) from FL-pretreated donors are acutely rejected.2 The fact that a single injection of CTLA4-Ig, a well-known inhibitor of B7/CD28 ligation, partially reversed the effect of donor FL treatment, as shown in the present study, indicates the importance of costimulatory molecule (B7 family) expression on donor APC (DC) in determining the outcome of liver transplantation. Deficiency or blockade of costimulatory molecule expression on donor APC may predispose to allograft survival and may play an important role in tolerance induction.
REFERENCES 1. Qian S, Demetris AJ, Murase N, et al: Hepatology 19:916, 1994 2. Qian S, Lu L, Fu F, et al: Transplantation 65:1590, 1998 3. Steptoe RJ, Fu F, Li W, et al: J Immunol 159:5483, 1997
RESULTS
Survival of liver grafts from FL-pretreated donors was prolonged significantly in the CTLA4-Ig group (MST 21 6 7.6 days [n 5 4]), compared with non-CTLA4-Ig controls (MST 4.6 6 0.5 days [n 5 6], P , .01). Livers from normal B10 donors were accepted indefinitely by normal C3H recipients (all six recipients survived .100 days). This indicates that a single dose of CTLA4-Ig can effectively, although not indefinitely, inhibit the effect of donor FL treatment. DISCUSSION
The mechanisms by which liver grafts are accepted spontaneously in allogeneic recipients in both mice and some © 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
4. van der Merwe PA, Bodian DL, Daenke S, et al: J Exp Med 185:393, 1997 5. Qian S, Lu L, Li Y, et al: J Immunol 158:4654, 1997 6. Thomson AW, Lu L, Murase N, et al: Stem Cells 13:622, 1995
From the Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. Address reprint requests to Dr Shiguang Qian, Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh Medical Center, E1540 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15213. 0041-1345/99/$–see front matter PII S0041-1345(98)01703-5 453
Transplantation Proceedings, 31, 453 (1999)
B
10 (H-2b) mouse livers are accepted spontaneously in C3H (H-2k) recipients without the requirement for immunosuppressive therapy (median survival time [MST] .100 days).1 However, livers from B10 donors pretreated with Flt3 ligand (FL), a recently cloned hematopoietic cytokine that dramatically increases the number of functional dendritic cells (DC) in lymphoid and nonlymphoid tissues, including the liver, are rejected acutely in normal C3H recipients (MST 5 days).2 This switch from tolerance to rejection is correlated with dramatic increases in DC with high cell surface expression of MHC class II and costimulatory molecules (CD40, CD80 [B7-1], and CD86 [B7-2]) isolated from the donor organ at the time of transplant.2,3 The objective of this study was to determine the role of B7/CD28 ligation in the conversion of liver transplant tolerance to rejection by donor treatment with FL using CTLA4-Ig, an immunoglobulin fusion protein that specifically blocks the ligands for CD28.4 This may lead to better understanding of the regulatory role of liver DC in transplant tolerance. MATERIALS AND METHODS C3H recipients were given CTLA4-Ig (Bristol-Myers Squibb, Princeton, NJ), 200 mg, as one intraperitoneal (IP) dose immediately after transplantation. Controls received no treatment. Livers were transplanted orthotopically from either normal B10 donors or B10 mice pretreated with FL (Immunex, Seattle, Wash; 10 mg/d IP for 10 consecutive days before transplantation).
other species are not fully understood. We have recently demonstrated that liver allograft acceptance is associated with high levels of CTL apoptotic death within the graftinfiltrating cell population.5 There is evidence that passenger leukocytes and their progenitors in liver grafts, including DC, may play a role in affecting the outcome of liver transplantation. Thus, normal liver-derived DC progenitors have the capacity to prolong graft survival.6 However, liver allografts containing high numbers of mature DC expressing high MHC class II and costimulatory molecules (CD40, CD80 [B7-1], and CD86 [B7-2]) from FL-pretreated donors are acutely rejected.2 The fact that a single injection of CTLA4-Ig, a well-known inhibitor of B7/CD28 ligation, partially reversed the effect of donor FL treatment, as shown in the present study, indicates the importance of costimulatory molecule (B7 family) expression on donor APC (DC) in determining the outcome of liver transplantation. Deficiency or blockade of costimulatory molecule expression on donor APC may predispose to allograft survival and may play an important role in tolerance induction.
REFERENCES 1. Qian S, Demetris AJ, Murase N, et al: Hepatology 19:916, 1994 2. Qian S, Lu L, Fu F, et al: Transplantation 65:1590, 1998 3. Steptoe RJ, Fu F, Li W, et al: J Immunol 159:5483, 1997
RESULTS
Survival of liver grafts from FL-pretreated donors was prolonged significantly in the CTLA4-Ig group (MST 21 6 7.6 days [n 5 4]), compared with non-CTLA4-Ig controls (MST 4.6 6 0.5 days [n 5 6], P , .01). Livers from normal B10 donors were accepted indefinitely by normal C3H recipients (all six recipients survived .100 days). This indicates that a single dose of CTLA4-Ig can effectively, although not indefinitely, inhibit the effect of donor FL treatment. DISCUSSION
The mechanisms by which liver grafts are accepted spontaneously in allogeneic recipients in both mice and some © 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
4. van der Merwe PA, Bodian DL, Daenke S, et al: J Exp Med 185:393, 1997 5. Qian S, Lu L, Li Y, et al: J Immunol 158:4654, 1997 6. Thomson AW, Lu L, Murase N, et al: Stem Cells 13:622, 1995
From the Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. Address reprint requests to Dr Shiguang Qian, Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh Medical Center, E1540 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15213. 0041-1345/99/$–see front matter PII S0041-1345(98)01703-5 453
Transplantation Proceedings, 31, 453 (1999)