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R. Parkman / Biol Blood Marrow Transplant 20 (2014) 749e751
Mixed Chimerism: Good News or Bad News? Robertson Parkman* Division of Blood and Marrow Transplantation, Children’s Hospital Los Angeles, Los Angeles, California
Article history: Received 1 April 2014 Accepted 2 April 2014
In the present issue of Biology of Blood and Marrow Transplantation, Benjamin et al. report the results of nonmyeloablative hematopoietic stem cell transplantation (HSCT) for patients with myelodysplastic syndrome and myeloproliferative neoplasms after conditioning with total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) [1]. The present report follows their previous reports of the use of TLI-ATG conditioning for the transplantation in patients with lymphoid malignancies and acute leukemia [2,3]. The recipients of the TLI-ATG regime have been characterized by an extremely low incidence of acute graft-versushost disease (GVHD) but a normal incidence of chronic GVHD. In the previous reports, the establishment of complete (> 95% donor T lymphocyte) chimerism has been associated with a reduced incidence of relapse, especially among recipients with lymphoid malignancies, regardless of their pre-HSCT status, whereas recipients with mixed chimerism (< 95% donor T lymphocytes) had a high rate of relapse. The same differences were seen in recipients with acute leukemia (an increased rate of relapse in recipients with mixed chimerism), although the overall relapse rates were higher. In the present study, the impact of both donor myeloid and lymphoid chimerism on the likelihood of relapse was examined. As in the previous studies, the presence of complete donor T lymphocyte chimerism was predictive of a decreased likelihood of relapse. Interestingly, the assessment of myeloid chimerism (CD15þ myeloid cells) determined that the presence of complete donor myeloid chimerism (> 95% donor CD15þ cells) was more predictive of a sustained remission than even complete donor T lymphocyte chimerism. The impact of myeloid chimerism as a predictor of the probability of relapse after TLI-ATG conditioning has not been previously reported. The basis for the protective effect of TLI-ATG against acute GVHD has been the subject of extensive preclinical evaluations, primarily in mice and in some human studies [4-6]. Central to the establishment of donor engraftment, with either complete or mixed chimerism, is the role of natural killer cells that express an invariant TCR receptor (iNKT cells). The recipient iNKT cells are relatively radioresistant, and, therefore, their relative frequency is markedly increased after TLI-ATG conditioning even though there is overall Financial disclosure: See Acknowledgments on page 751. * Correspondence and reprint requests: Robertson Parkman, MD, Division of Blood and Marrow Transplantation, Children’s Hospital Los Angeles, 4650 Sunset Boulevard, Mail Stop 62, Los Angeles, CA 90027. E-mail address: [email protected] 1083-8791/$ e see front matter Ó 2014 American Society for Blood and Marrow Transplantation. http://dx.doi.org/10.1016/j.bbmt.2014.04.001
lymphopenia. The recipients of TLI-ATG HSCT receive CD34þ cells isolated from the cytokine-mobilized donor peripheral blood stem cells plus defined doses of CD3 T lymphocytes, which contain iNKT cells. Both donor and recipient iNKT cells are essential for the establishment of donor hematopoietic stem cell engraftment without the development of acute GVHD. The iNKT cells are activated by the TLI and other agents to produce IL-4, which activates both donor and recipient regulatory T lymphocytes (Treg), which then produce the immunosuppressant molecule, IL-10, resulting in a lack of donor hematopoietic stem cell rejection. Murine experiments have defined the absolute requirement for donor and recipient iNKT cells, IL-4, Treg lymphocytes, and IL-10 for the establishment of either complete or mixed donor chimerism. Of interest is the fact that TLI-ATG conditioning has not reduced the incidence of chronic GVHD, as most analyses of chronic GVHD have indicated that the presence of acute GVHD is the major predictor of chronic GVHD [7]. The presence of chronic GVHD after TLI-ATG suggests that the preparative regime may have a direct role in the pathogenesis of chronic GVHD. The TLI-ATG conditioning regime has also been used as an adjunct to HSCT in the context of renal transplantation with the goal of developing recipient tolerance to the donor renal graft and, therefore, the possibility of withdrawing all immunosuppressive drugs. After related renal transplantation, recipients undergo conditioning with TLI-ATG and the transplantation of defined doses of CD34þ cells isolated from mobilized donor peripheral blood stem cells and defined doses of CD3 T lymphocytes, depending upon whether the donor is HLA identical or not [8,9]. The recipients received routine renal transplantation immunosuppression, including mycophenolate mofetil and cyclosporine. The establishment of sustained, but not necessarily permanent, mixed chimerism (donor T lymphocytes < 95% by day 100) has resulted in the complete withdrawal of all immunosuppressive drugs in some recipients. The goal of the TLI-ATG HSCT is not complete donor lymphoid chimerism, as it would be associated with significant post-transplantation immunodeficiency and the possibility of opportunistic infections. Recipients who do not develop mixed chimerism, continue on their routine post-transplantation immunosuppression. In mice, the establishment of sustained donor mixed donor chimerism results in bidirectional tolerance that results in graft persistence without ongoing immunosuppression. Thus, the presence of mixed chimerism after HSCT is either to be desired (as in the case of renal transplantation) or is to be avoided (as is the case in hematological malignancies), depending upon the clinical setting. The basis for the control of the TLI-ATG regime is the quantification of both the hematopoietic stem cells and T lymphocyte doses, because both can influence whether complete or mixed chimerism is more likely to be achieved. In the future, HSCT will have increasing use as an immunomodulatory agent, the
R. Parkman / Biol Blood Marrow Transplant 20 (2014) 749e751
goal of which will depend upon the clinical setting. The use of defined doses of both hematopoietic stem cells and T lymphocytes will be necessary to fine-tune the degree of donor chimerism after HSCT. ACKNOWLEDGMENTS Conflict of interest statement: There are no conflicts of interest to report. Financial diclosure: The authors have nothing to disclose. REFERENCES 1. Benjamin J, Chhabra S, Kohrt HE, et al. Total lymphoid irradiationantithymocyte globulin conditioning and allogeneic transplantation for patients with myelodysplastic syndromes and myeloproliferative neoplasms. Biol Blood Marrow Transplant. 2014;20:837-843. 2. Lowsky R, Takahashi I, Liu YP, et al. Protective conditioning for acute graft-versus-host disease. N Engl J Med. 2005;353:1321-1341.
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3. Kohrt HE, Turnbull BB, Heydari K, et al. TLI and ATG conditioning with low risk of graft-versus-host disease retains antitumor reactions after allogeneic hematopoietic cell transplantation from related and unrelated donors. Blood. 2009;114:1099-1109. 4. Pillai AB, George RI, Dutt S, et al. Host NKT cells can prevent graft-versushost disease and permit graft antitumor activity after bone marrow transplantation. J Immunol. 2007;178:6242-6251. 5. Pillai AB, George TI, Dutt S, Strober S. Host natural killer T cells induce an interleukin-4-dependent expansion of donor CD4þCD25þFoxp3þ T regulatory cells that protects against graft-versus-host disease. Blood. 2009;113:4458-4467. 6. Kohrt HE, Pillai AB, Lowsky R, Strober S. NKT cells, Treg, and their interactions in bone marrow transplantation. Eur J Immunol. 2010;40: 1862-1869. 7. Blazar BR, Murphy WJ, Abedi M. Advances in graft-versus-host disease biology and therapy. Nat Rev Immunol. 2012;12:443-458. 8. Scandling JD, Busque S, Dejbakhsh-Jones S, et al. Tolerance and chimerism after renal and hemopoietic-cell transplantation. N Engl J Med. 2008;358:362-368. 9. Scandling JD, Busque S, Shizuru JA, et al. Induced immune tolerance for kidney transplantation. N Engl J Med. 2011;365:1359-1360.
R. Parkman / Biol Blood Marrow Transplant 20 (2014) 749e751
Mixed Chimerism: Good News or Bad News? Robertson Parkman* Division of Blood and Marrow Transplantation, Children’s Hospital Los Angeles, Los Angeles, California
Article history: Received 1 April 2014 Accepted 2 April 2014
In the present issue of Biology of Blood and Marrow Transplantation, Benjamin et al. report the results of nonmyeloablative hematopoietic stem cell transplantation (HSCT) for patients with myelodysplastic syndrome and myeloproliferative neoplasms after conditioning with total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) [1]. The present report follows their previous reports of the use of TLI-ATG conditioning for the transplantation in patients with lymphoid malignancies and acute leukemia [2,3]. The recipients of the TLI-ATG regime have been characterized by an extremely low incidence of acute graft-versushost disease (GVHD) but a normal incidence of chronic GVHD. In the previous reports, the establishment of complete (> 95% donor T lymphocyte) chimerism has been associated with a reduced incidence of relapse, especially among recipients with lymphoid malignancies, regardless of their pre-HSCT status, whereas recipients with mixed chimerism (< 95% donor T lymphocytes) had a high rate of relapse. The same differences were seen in recipients with acute leukemia (an increased rate of relapse in recipients with mixed chimerism), although the overall relapse rates were higher. In the present study, the impact of both donor myeloid and lymphoid chimerism on the likelihood of relapse was examined. As in the previous studies, the presence of complete donor T lymphocyte chimerism was predictive of a decreased likelihood of relapse. Interestingly, the assessment of myeloid chimerism (CD15þ myeloid cells) determined that the presence of complete donor myeloid chimerism (> 95% donor CD15þ cells) was more predictive of a sustained remission than even complete donor T lymphocyte chimerism. The impact of myeloid chimerism as a predictor of the probability of relapse after TLI-ATG conditioning has not been previously reported. The basis for the protective effect of TLI-ATG against acute GVHD has been the subject of extensive preclinical evaluations, primarily in mice and in some human studies [4-6]. Central to the establishment of donor engraftment, with either complete or mixed chimerism, is the role of natural killer cells that express an invariant TCR receptor (iNKT cells). The recipient iNKT cells are relatively radioresistant, and, therefore, their relative frequency is markedly increased after TLI-ATG conditioning even though there is overall Financial disclosure: See Acknowledgments on page 751. * Correspondence and reprint requests: Robertson Parkman, MD, Division of Blood and Marrow Transplantation, Children’s Hospital Los Angeles, 4650 Sunset Boulevard, Mail Stop 62, Los Angeles, CA 90027. E-mail address: [email protected] 1083-8791/$ e see front matter Ó 2014 American Society for Blood and Marrow Transplantation. http://dx.doi.org/10.1016/j.bbmt.2014.04.001
lymphopenia. The recipients of TLI-ATG HSCT receive CD34þ cells isolated from the cytokine-mobilized donor peripheral blood stem cells plus defined doses of CD3 T lymphocytes, which contain iNKT cells. Both donor and recipient iNKT cells are essential for the establishment of donor hematopoietic stem cell engraftment without the development of acute GVHD. The iNKT cells are activated by the TLI and other agents to produce IL-4, which activates both donor and recipient regulatory T lymphocytes (Treg), which then produce the immunosuppressant molecule, IL-10, resulting in a lack of donor hematopoietic stem cell rejection. Murine experiments have defined the absolute requirement for donor and recipient iNKT cells, IL-4, Treg lymphocytes, and IL-10 for the establishment of either complete or mixed donor chimerism. Of interest is the fact that TLI-ATG conditioning has not reduced the incidence of chronic GVHD, as most analyses of chronic GVHD have indicated that the presence of acute GVHD is the major predictor of chronic GVHD [7]. The presence of chronic GVHD after TLI-ATG suggests that the preparative regime may have a direct role in the pathogenesis of chronic GVHD. The TLI-ATG conditioning regime has also been used as an adjunct to HSCT in the context of renal transplantation with the goal of developing recipient tolerance to the donor renal graft and, therefore, the possibility of withdrawing all immunosuppressive drugs. After related renal transplantation, recipients undergo conditioning with TLI-ATG and the transplantation of defined doses of CD34þ cells isolated from mobilized donor peripheral blood stem cells and defined doses of CD3 T lymphocytes, depending upon whether the donor is HLA identical or not [8,9]. The recipients received routine renal transplantation immunosuppression, including mycophenolate mofetil and cyclosporine. The establishment of sustained, but not necessarily permanent, mixed chimerism (donor T lymphocytes < 95% by day 100) has resulted in the complete withdrawal of all immunosuppressive drugs in some recipients. The goal of the TLI-ATG HSCT is not complete donor lymphoid chimerism, as it would be associated with significant post-transplantation immunodeficiency and the possibility of opportunistic infections. Recipients who do not develop mixed chimerism, continue on their routine post-transplantation immunosuppression. In mice, the establishment of sustained donor mixed donor chimerism results in bidirectional tolerance that results in graft persistence without ongoing immunosuppression. Thus, the presence of mixed chimerism after HSCT is either to be desired (as in the case of renal transplantation) or is to be avoided (as is the case in hematological malignancies), depending upon the clinical setting. The basis for the control of the TLI-ATG regime is the quantification of both the hematopoietic stem cells and T lymphocyte doses, because both can influence whether complete or mixed chimerism is more likely to be achieved. In the future, HSCT will have increasing use as an immunomodulatory agent, the
R. Parkman / Biol Blood Marrow Transplant 20 (2014) 749e751
goal of which will depend upon the clinical setting. The use of defined doses of both hematopoietic stem cells and T lymphocytes will be necessary to fine-tune the degree of donor chimerism after HSCT. ACKNOWLEDGMENTS Conflict of interest statement: There are no conflicts of interest to report. Financial diclosure: The authors have nothing to disclose. REFERENCES 1. Benjamin J, Chhabra S, Kohrt HE, et al. Total lymphoid irradiationantithymocyte globulin conditioning and allogeneic transplantation for patients with myelodysplastic syndromes and myeloproliferative neoplasms. Biol Blood Marrow Transplant. 2014;20:837-843. 2. Lowsky R, Takahashi I, Liu YP, et al. Protective conditioning for acute graft-versus-host disease. N Engl J Med. 2005;353:1321-1341.
751
3. Kohrt HE, Turnbull BB, Heydari K, et al. TLI and ATG conditioning with low risk of graft-versus-host disease retains antitumor reactions after allogeneic hematopoietic cell transplantation from related and unrelated donors. Blood. 2009;114:1099-1109. 4. Pillai AB, George RI, Dutt S, et al. Host NKT cells can prevent graft-versushost disease and permit graft antitumor activity after bone marrow transplantation. J Immunol. 2007;178:6242-6251. 5. Pillai AB, George TI, Dutt S, Strober S. Host natural killer T cells induce an interleukin-4-dependent expansion of donor CD4þCD25þFoxp3þ T regulatory cells that protects against graft-versus-host disease. Blood. 2009;113:4458-4467. 6. Kohrt HE, Pillai AB, Lowsky R, Strober S. NKT cells, Treg, and their interactions in bone marrow transplantation. Eur J Immunol. 2010;40: 1862-1869. 7. Blazar BR, Murphy WJ, Abedi M. Advances in graft-versus-host disease biology and therapy. Nat Rev Immunol. 2012;12:443-458. 8. Scandling JD, Busque S, Dejbakhsh-Jones S, et al. Tolerance and chimerism after renal and hemopoietic-cell transplantation. N Engl J Med. 2008;358:362-368. 9. Scandling JD, Busque S, Shizuru JA, et al. Induced immune tolerance for kidney transplantation. N Engl J Med. 2011;365:1359-1360.
