- Email: [email protected]
Road to transplantation tolerance: role of T-suppressor lymphocytes in solid-organ transplantation
Road to Transplantation Tolerance: Role of T-Suppressor Lymphocytes in Solid-Organ Transplantation R. Cortesini
A
Allospecific T-suppressor cells were detected by flow cytometry determination of the ability of recipient CD8⫹ CD28⫺ T cells to inhibit CD80 and CD86 expression on donor antigen presenting cells (APC) co-incubated with CD40L-transfected cells as described.1 Allospecific T-helper cells were detected by limiting dilution analysis of the precursor frequency of recipient T cells displaying blastogenic responses when stimulated with autologous APC pulsed with synthetic 20-meric peptides corresponding to the sequence of the variable region of donor HLA-DR BI molecules.2,3 Anti-HLA alloantibodies were studied using ELISA plates from One Lambda (Lambda Antigen Tray ELISA).
sor cells (Ts), which are crucial to allogeneic tolerance. We demonstrated that within the CD8⫹ subset of lymphocytes there is a population that has the CD8⫹ CD28⫺ phenotype and has suppressor function. These T cells interact directly with APC, recognizing MHC class I/peptide complexes on their surface; the Ts inhibit the activation of NFB and transcription of co-stimulatory molecules by APC, rendering them unable to stimulate the activation of T-helper cells. Based on the knowledge of the mechanism of action of Ts, we developed a reliable method for monitoring allospecific Ts in recipients of heart, kidney, or liver allografts. Our method consists of quantitating the ability of T cells from the recipient’s blood to inhibit the transcription of costimulatory molecules on APC from the donor. Serial monitoring of recipients with heart, kidney, and liver transplants has demonstrated that recipients who display donorspecific Ts remain in quiescence. Based on the results of Ts studies we have been able to diminish significantly the number and amount of immunosuppressive drugs administered to transplant recipients. Patients who were switched to monotherapy maintained excellent function of the transplant over 6 to 12 months of follow-up. Our study demonstrates that identification of patients who have developed a state of functional tolerance permits the avoidance of many of the complications associated with the use of high doses of immunosuppressive drugs. This avenue of research has the potential of generating a new strategy for induction of immunological tolerance.
RESULTS AND DISCUSSION
REFERENCES
We have developed powerful immunological strategies for monitoring alloimmune reactivity in transplant patients. We demonstrated in the past that allograft rejection is mediated by T cells recognizing allopeptides derived from processing of donor necrotic cells by host dendritic cells. Measuring recipients’ reactivity to donor MHC class II peptides we showed that both acute and chronic rejection can be accurately predicted. More recently, we made a step forward by discovering the identity and function of T-suppres-
1. Ciubotariu R, Li J, Colovai AI, et al: Hum Immunol 62:470, 2001 2. Liu Z, Colovai AI, Tugulea S, et al: J Clin Invest 98:1150, 1996 3. Ciubotariu R, Liu Z, Colovai AI, et al: J Clin Invest 101:398, 1998
LTHOUGH significant progress has been made over the last decades in the management of organ allograft recipients, the long-term success of transplantation is threatened by chronic rejection, malignancies, infections, and cardiovascular complications related to immunosuppressive treatment. Tailoring of immunosuppression to the patient’s individual needs to reduce the toxicity and risks associated with the use of various drugs remains a major goal in clinical transplantation. Achievement of this goal, however, requires a better understanding of mechanisms that drive the patient’s potential to reject or tolerate the graft. To achieve this goal we have undertaken a serial evaluation of allospecific T-helper and suppressor cells, as well as anti-HLA antibodies, in a population of 16 recipients of renal allografts and 21 recipients of liver allografts. We now present the results of these studies. MATERIALS AND METHODS
© 2002 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 34, 1999 (2002)
From the University of Rome “La Sapienza,” Rome, Italy. Address reprint requests to R. Cortesini, Columbia University, Department of Pathology, 630 West 168 Street—P&S 14-401, New York, NY 10032.
0041-1345/02/$–see front matter PII S0041-1345(02)02828-2 1999
A
Allospecific T-suppressor cells were detected by flow cytometry determination of the ability of recipient CD8⫹ CD28⫺ T cells to inhibit CD80 and CD86 expression on donor antigen presenting cells (APC) co-incubated with CD40L-transfected cells as described.1 Allospecific T-helper cells were detected by limiting dilution analysis of the precursor frequency of recipient T cells displaying blastogenic responses when stimulated with autologous APC pulsed with synthetic 20-meric peptides corresponding to the sequence of the variable region of donor HLA-DR BI molecules.2,3 Anti-HLA alloantibodies were studied using ELISA plates from One Lambda (Lambda Antigen Tray ELISA).
sor cells (Ts), which are crucial to allogeneic tolerance. We demonstrated that within the CD8⫹ subset of lymphocytes there is a population that has the CD8⫹ CD28⫺ phenotype and has suppressor function. These T cells interact directly with APC, recognizing MHC class I/peptide complexes on their surface; the Ts inhibit the activation of NFB and transcription of co-stimulatory molecules by APC, rendering them unable to stimulate the activation of T-helper cells. Based on the knowledge of the mechanism of action of Ts, we developed a reliable method for monitoring allospecific Ts in recipients of heart, kidney, or liver allografts. Our method consists of quantitating the ability of T cells from the recipient’s blood to inhibit the transcription of costimulatory molecules on APC from the donor. Serial monitoring of recipients with heart, kidney, and liver transplants has demonstrated that recipients who display donorspecific Ts remain in quiescence. Based on the results of Ts studies we have been able to diminish significantly the number and amount of immunosuppressive drugs administered to transplant recipients. Patients who were switched to monotherapy maintained excellent function of the transplant over 6 to 12 months of follow-up. Our study demonstrates that identification of patients who have developed a state of functional tolerance permits the avoidance of many of the complications associated with the use of high doses of immunosuppressive drugs. This avenue of research has the potential of generating a new strategy for induction of immunological tolerance.
RESULTS AND DISCUSSION
REFERENCES
We have developed powerful immunological strategies for monitoring alloimmune reactivity in transplant patients. We demonstrated in the past that allograft rejection is mediated by T cells recognizing allopeptides derived from processing of donor necrotic cells by host dendritic cells. Measuring recipients’ reactivity to donor MHC class II peptides we showed that both acute and chronic rejection can be accurately predicted. More recently, we made a step forward by discovering the identity and function of T-suppres-
1. Ciubotariu R, Li J, Colovai AI, et al: Hum Immunol 62:470, 2001 2. Liu Z, Colovai AI, Tugulea S, et al: J Clin Invest 98:1150, 1996 3. Ciubotariu R, Liu Z, Colovai AI, et al: J Clin Invest 101:398, 1998
LTHOUGH significant progress has been made over the last decades in the management of organ allograft recipients, the long-term success of transplantation is threatened by chronic rejection, malignancies, infections, and cardiovascular complications related to immunosuppressive treatment. Tailoring of immunosuppression to the patient’s individual needs to reduce the toxicity and risks associated with the use of various drugs remains a major goal in clinical transplantation. Achievement of this goal, however, requires a better understanding of mechanisms that drive the patient’s potential to reject or tolerate the graft. To achieve this goal we have undertaken a serial evaluation of allospecific T-helper and suppressor cells, as well as anti-HLA antibodies, in a population of 16 recipients of renal allografts and 21 recipients of liver allografts. We now present the results of these studies. MATERIALS AND METHODS
© 2002 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 34, 1999 (2002)
From the University of Rome “La Sapienza,” Rome, Italy. Address reprint requests to R. Cortesini, Columbia University, Department of Pathology, 630 West 168 Street—P&S 14-401, New York, NY 10032.
0041-1345/02/$–see front matter PII S0041-1345(02)02828-2 1999