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The Epic Race to Immune Reconstitution
THE BOTTOM LINE
The Epic Race to Immune Reconstitution Michael Verneris, John E. Wagner Regardless of the hematopoietic stem cell (HSC) source, reconstitution of adaptive immunity is arguably the last great barrier to successful allogeneic hematopoietic cell transplantation. Early after transplantation, prolonged lymphocytopenia, and profound immune dysfunction result in infectious complications that are frequent and often life threatening [1]. In addition, delayed immune recovery may also increase the risk of relapse in patients treated for malignant disease [2,3]. The number of variables in the transplant recipient, such as patient age, graft source, HLA match, intensity of conditioning, and immune suppressive regimens make it difficult to identify the specific impact of a single variable. In addition, the absence of validated functional immune reconstitution assays hinders progress in the field. In this issue of BBMT, Jacobson and colleagues [4] tackle the clinical question of whether immune reconstitution in adult recipients of HLA mismatched umbilical cord blood (UCB) differs from that in adult recipients of HLA matched unrelated peripheral blood (PB) transplantation. The data presented suggest that there may indeed be a significant delay in immune recovery after UCB transplantation. During the first 6-month period following transplantation, the absolute number of T cells and naive CD41 and CD41CD251 T regulatory cell subsets were markedly reduced, whereas the number of B and natural killer cells was significantly higher in recipients of UCB compared to recipients of PB. Importantly, these differences were associated with higher rates of infectious complications in the UCB group (59% versus 8%, P \ .0001), with increases in bacterial, viral, and fungal pathogens during the same period. Despite these differences, risks of nonrelapse mortality and 2-year progression-free survival were similar between the 2 groups. As expected, based on prior reports, the inci-
From the Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota. Correspondence and reprint requests: John E. Wagner, MD, Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, MN 55455 (e-mail: [email protected]). Received February 6, 2012; accepted February 8, 2012 Ó 2012 American Society for Blood and Marrow Transplantation 1083-8791/$36.00 doi:10.1016/j.bbmt.2012.02.003
dence of chronic graft-versus-host disease was higher after PB transplantation. But, is UCB truly inferior to PB in terms of immune recovery? It is certainly possible. Clearly, there are known differences in neonatal and adult blood with respect to numbers of naive and antigen experienced T cells. There are also functional differences between UCB and PB T cells, with the UCB showing a reduced propensity to elaborate cytokines in vitro [5]. As well, it should be taken into account that there are also differences in the immune profile and function of PB before and after granulocytecolony stimulating factor mobilization, including more Th2 skewing [6] and reduced natural killer cytotoxicity [7]. In addition to differences in the lymphocyte compartment, recent data suggest that the stem cells themselves differ between adult and UCB, with UCB HSCs giving rise to T cells that are more tolerogenic [8]. Thus, it is plausible to consider that graft-intrinsic properties may account for the above findings by Jacobson et al. The study by Jacobsen et al., however, only tells us that the ‘‘treatment package’’ is associated with a slower pace of immune recovery, as measured by cell surface markers and supported by infectious disease complications. In particular, UCB recipients were conditioned with melphalan, fludarabine, and antithymocyte globulin (ATG) and PB recipients with busulfan and fludarabine without ATG. Similarly, graft-versus-host disease immunoprophylaxis also differed with most UCB recipients treated with sirolimus and tacrolimus and PB recipients, sirolimus, tacrolimus, and methotrexate. As recognized by the authors, these variables must be taken into consideration. So, we are left unable to answer the question—is delayed immune reconstitution after UCB transplant because of some intrinsic factor unique to UCB? Maybe, but maybe not. The current literature is mixed. In a recent study by Renard et al. [9] rapid T cell reconstitution was observed in children transplanted with UCB the absence of ATG. As conditioning regimens and graft-versus-host disease prophylaxis strategies evolve, the impact on both short- and long-term immune recovery should be assessed, optimally, by modifying one variable at a time. Furthermore, what is the best way to assess immune reconstitution? The fact that T cells are present after transplantation is important, does not necessarily 493
494
E. W. Petersdorf
Biol Blood Marrow Transplant 18:493-496, 2012
indicate normal function. Today, functional assays such as with tetramer staining, intracellular cytokine staining, and degranulation assays, are becoming more readily available and allow us to functionally interrogate lymphocyte subpopulations. These assessments, if validated as predictors of infection and relapse, will not only help elucidate the impact of various graft-intrinsic and extrinsic factors on the kinetics of immune recovery, but may also help us identify those patients at highest risk for these complications. The article by Jacobson et al. [4] challenges us further to identify what factor or factors may be responsible for the apparent delay in adaptive immunity observed in their patients undergoing UCB transplantation. The tools now exist to better assess immune function and perhaps overcome this brick wall, previously limiting our ability to understand the myriad of factors negatively influencing immune reconstitution. What are ‘‘brick walls’’ anyway? As we are told by Randy Pausch in The Last Lecture, ‘‘Brick walls . are there to give us a chance to show how badly we want something . brick walls are there to stop the other people!’’ [Not us!] It’s time to remove this wall and finally figure out how to enhance the pace of immune reconstitution . and win the race.’’
REFERENCES 1. Hamza NS, Lisgaris M, Yadavalli G, et al. Kinetics of myeloid and lymphocyte recovery and infectious complications after unrelated umbilical cord blood versus HLA-matched unrelated donor allogeneic transplantation in adults. Br J Haematol. 2004;124:488-498. 2. Parkman R, Cohen G, Carter SL, et al. Successful immune reconstitution decreases leukemic relapse and improves survival in recipients of unrelated cord blood transplantation. Biol Blood Marrow Transplant. 2006;12:919-927. 3. Savani BN, Mielke S, Adams S, et al. Rapid natural killer cell recovery determines outcome after T-cell-depleted HLA-identical stem cell transplantation in patients with myeloid leukemias but not with acute lymphoblastic leukemia. Leukemia. 2007;21:2145-2152. 4. Jacobson CA, Turki AT, McDonough SM, et al. Immune Reconstitution after Double Umbilical Cord Blood Stem Cell Transplantation: Comparison with Unrelated Peripheral Blood Stem Cell Transplantation. Biol Blood Marrow Transplant. 2012;18:565-574. 5. Kaminski BA, Kadereit S, Miller RE, et al. Reduced expression of NFAT-associated genes in UCB versus adult CD41 T lymphocytes during primary stimulation. Blood. 2003;102:4608-4617. 6. Klangsinsirikul P, Russell NH. Peripheral blood stem cell harvests from G-CSF-stimulated donors contain a skewed Th2 CD4 phenotype and a predominance of type 2 dendritic cells. Exp Hematol. 2002;30:495-501. 7. Su YC, Li SC, Hsu CK, et al. G-CSF downregulates natural killer cell-mediated cytotoxicity in donors for hematopoietic SCT. Bone Marrow Transplant. 2012;47:73-81. 8. Mold JE, Venkatasubrahmanyam S, Burt TD, et al. Fetal and adult hematopoietic stem cells give rise to distinct T cell lineages in humans. Science. 2010;330:1695-1699. 9. Renard C, Barlogis V, Mialou V, et al. Lymphocyte subset reconstitution after unrelated cord blood or bone marrow transplantation in children. Br J Haematol. 2011;152:322-330.
Of Genes, Blocks, and Haplotypes Effie W. Petersdorf The MHC is home to a series of genes that have highly coordinated functions in the immune response. Genes involved in antigen presentation (HLA-A, C, B, DR, DQ, and DP) reside near genes involved in antigen processing (TAP), the innate response (MICA, MICB), stress and inflammation (TNF, LTA, LST), and regulatory receptors (NOTCH4). Although the class I, III, and II regions are each distinguished by their unique genetic landscape, variation across the MHC is highly organized into haplotypes that link
From the Fred Hutchinson Cancer Research Center, Seattle, Washington. Financial disclosure: See Acknowledgment on page 495. Correspondence and reprint requests: John E. Wagner, MD, Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, MN 55455 (e-mail: [email protected]). Received January 24, 2012; accepted January 24, 2012 Ó 2012 American Society for Blood and Marrow Transplantation 1083-8791/$36.00 doi:10.1016/j.bbmt.2012.01.016
genes from the extended class I through to the extended class II region. Much like a patchwork quilt where individual blocks can be configured in different ways to create unique patterns, the MHC has segments or blocks of highly conserved sequences that are characteristic of haplotypes. A key to understanding the MHC is the nature of its ‘‘blockiness’’ and haplotypic associations. The study by Bettens et al. [1] examined 2 genes that reside in distinct regions of the MHC and their role in transplantation outcome: the TNF segment in the class III region, and HLA-DP in class II. At the centromeric end of the HLA region resides HLA-DP, a highly polymorphic locus (over 152 unique alleles recognized as of January 2012; http:// www.ebi.ac.uk/imgt/hla/) that is firmly established as a classical transplantation locus [2,3]. Although donor matching is associated with a lower risk of graft-versus-host disease (GVHD), practically, prospective donor matching is difficult because of the weaker linkage disequilibrium that leads to mismatch
The Epic Race to Immune Reconstitution Michael Verneris, John E. Wagner Regardless of the hematopoietic stem cell (HSC) source, reconstitution of adaptive immunity is arguably the last great barrier to successful allogeneic hematopoietic cell transplantation. Early after transplantation, prolonged lymphocytopenia, and profound immune dysfunction result in infectious complications that are frequent and often life threatening [1]. In addition, delayed immune recovery may also increase the risk of relapse in patients treated for malignant disease [2,3]. The number of variables in the transplant recipient, such as patient age, graft source, HLA match, intensity of conditioning, and immune suppressive regimens make it difficult to identify the specific impact of a single variable. In addition, the absence of validated functional immune reconstitution assays hinders progress in the field. In this issue of BBMT, Jacobson and colleagues [4] tackle the clinical question of whether immune reconstitution in adult recipients of HLA mismatched umbilical cord blood (UCB) differs from that in adult recipients of HLA matched unrelated peripheral blood (PB) transplantation. The data presented suggest that there may indeed be a significant delay in immune recovery after UCB transplantation. During the first 6-month period following transplantation, the absolute number of T cells and naive CD41 and CD41CD251 T regulatory cell subsets were markedly reduced, whereas the number of B and natural killer cells was significantly higher in recipients of UCB compared to recipients of PB. Importantly, these differences were associated with higher rates of infectious complications in the UCB group (59% versus 8%, P \ .0001), with increases in bacterial, viral, and fungal pathogens during the same period. Despite these differences, risks of nonrelapse mortality and 2-year progression-free survival were similar between the 2 groups. As expected, based on prior reports, the inci-
From the Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota. Correspondence and reprint requests: John E. Wagner, MD, Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, MN 55455 (e-mail: [email protected]). Received February 6, 2012; accepted February 8, 2012 Ó 2012 American Society for Blood and Marrow Transplantation 1083-8791/$36.00 doi:10.1016/j.bbmt.2012.02.003
dence of chronic graft-versus-host disease was higher after PB transplantation. But, is UCB truly inferior to PB in terms of immune recovery? It is certainly possible. Clearly, there are known differences in neonatal and adult blood with respect to numbers of naive and antigen experienced T cells. There are also functional differences between UCB and PB T cells, with the UCB showing a reduced propensity to elaborate cytokines in vitro [5]. As well, it should be taken into account that there are also differences in the immune profile and function of PB before and after granulocytecolony stimulating factor mobilization, including more Th2 skewing [6] and reduced natural killer cytotoxicity [7]. In addition to differences in the lymphocyte compartment, recent data suggest that the stem cells themselves differ between adult and UCB, with UCB HSCs giving rise to T cells that are more tolerogenic [8]. Thus, it is plausible to consider that graft-intrinsic properties may account for the above findings by Jacobson et al. The study by Jacobsen et al., however, only tells us that the ‘‘treatment package’’ is associated with a slower pace of immune recovery, as measured by cell surface markers and supported by infectious disease complications. In particular, UCB recipients were conditioned with melphalan, fludarabine, and antithymocyte globulin (ATG) and PB recipients with busulfan and fludarabine without ATG. Similarly, graft-versus-host disease immunoprophylaxis also differed with most UCB recipients treated with sirolimus and tacrolimus and PB recipients, sirolimus, tacrolimus, and methotrexate. As recognized by the authors, these variables must be taken into consideration. So, we are left unable to answer the question—is delayed immune reconstitution after UCB transplant because of some intrinsic factor unique to UCB? Maybe, but maybe not. The current literature is mixed. In a recent study by Renard et al. [9] rapid T cell reconstitution was observed in children transplanted with UCB the absence of ATG. As conditioning regimens and graft-versus-host disease prophylaxis strategies evolve, the impact on both short- and long-term immune recovery should be assessed, optimally, by modifying one variable at a time. Furthermore, what is the best way to assess immune reconstitution? The fact that T cells are present after transplantation is important, does not necessarily 493
494
E. W. Petersdorf
Biol Blood Marrow Transplant 18:493-496, 2012
indicate normal function. Today, functional assays such as with tetramer staining, intracellular cytokine staining, and degranulation assays, are becoming more readily available and allow us to functionally interrogate lymphocyte subpopulations. These assessments, if validated as predictors of infection and relapse, will not only help elucidate the impact of various graft-intrinsic and extrinsic factors on the kinetics of immune recovery, but may also help us identify those patients at highest risk for these complications. The article by Jacobson et al. [4] challenges us further to identify what factor or factors may be responsible for the apparent delay in adaptive immunity observed in their patients undergoing UCB transplantation. The tools now exist to better assess immune function and perhaps overcome this brick wall, previously limiting our ability to understand the myriad of factors negatively influencing immune reconstitution. What are ‘‘brick walls’’ anyway? As we are told by Randy Pausch in The Last Lecture, ‘‘Brick walls . are there to give us a chance to show how badly we want something . brick walls are there to stop the other people!’’ [Not us!] It’s time to remove this wall and finally figure out how to enhance the pace of immune reconstitution . and win the race.’’
REFERENCES 1. Hamza NS, Lisgaris M, Yadavalli G, et al. Kinetics of myeloid and lymphocyte recovery and infectious complications after unrelated umbilical cord blood versus HLA-matched unrelated donor allogeneic transplantation in adults. Br J Haematol. 2004;124:488-498. 2. Parkman R, Cohen G, Carter SL, et al. Successful immune reconstitution decreases leukemic relapse and improves survival in recipients of unrelated cord blood transplantation. Biol Blood Marrow Transplant. 2006;12:919-927. 3. Savani BN, Mielke S, Adams S, et al. Rapid natural killer cell recovery determines outcome after T-cell-depleted HLA-identical stem cell transplantation in patients with myeloid leukemias but not with acute lymphoblastic leukemia. Leukemia. 2007;21:2145-2152. 4. Jacobson CA, Turki AT, McDonough SM, et al. Immune Reconstitution after Double Umbilical Cord Blood Stem Cell Transplantation: Comparison with Unrelated Peripheral Blood Stem Cell Transplantation. Biol Blood Marrow Transplant. 2012;18:565-574. 5. Kaminski BA, Kadereit S, Miller RE, et al. Reduced expression of NFAT-associated genes in UCB versus adult CD41 T lymphocytes during primary stimulation. Blood. 2003;102:4608-4617. 6. Klangsinsirikul P, Russell NH. Peripheral blood stem cell harvests from G-CSF-stimulated donors contain a skewed Th2 CD4 phenotype and a predominance of type 2 dendritic cells. Exp Hematol. 2002;30:495-501. 7. Su YC, Li SC, Hsu CK, et al. G-CSF downregulates natural killer cell-mediated cytotoxicity in donors for hematopoietic SCT. Bone Marrow Transplant. 2012;47:73-81. 8. Mold JE, Venkatasubrahmanyam S, Burt TD, et al. Fetal and adult hematopoietic stem cells give rise to distinct T cell lineages in humans. Science. 2010;330:1695-1699. 9. Renard C, Barlogis V, Mialou V, et al. Lymphocyte subset reconstitution after unrelated cord blood or bone marrow transplantation in children. Br J Haematol. 2011;152:322-330.
Of Genes, Blocks, and Haplotypes Effie W. Petersdorf The MHC is home to a series of genes that have highly coordinated functions in the immune response. Genes involved in antigen presentation (HLA-A, C, B, DR, DQ, and DP) reside near genes involved in antigen processing (TAP), the innate response (MICA, MICB), stress and inflammation (TNF, LTA, LST), and regulatory receptors (NOTCH4). Although the class I, III, and II regions are each distinguished by their unique genetic landscape, variation across the MHC is highly organized into haplotypes that link
From the Fred Hutchinson Cancer Research Center, Seattle, Washington. Financial disclosure: See Acknowledgment on page 495. Correspondence and reprint requests: John E. Wagner, MD, Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, MN 55455 (e-mail: [email protected]). Received January 24, 2012; accepted January 24, 2012 Ó 2012 American Society for Blood and Marrow Transplantation 1083-8791/$36.00 doi:10.1016/j.bbmt.2012.01.016
genes from the extended class I through to the extended class II region. Much like a patchwork quilt where individual blocks can be configured in different ways to create unique patterns, the MHC has segments or blocks of highly conserved sequences that are characteristic of haplotypes. A key to understanding the MHC is the nature of its ‘‘blockiness’’ and haplotypic associations. The study by Bettens et al. [1] examined 2 genes that reside in distinct regions of the MHC and their role in transplantation outcome: the TNF segment in the class III region, and HLA-DP in class II. At the centromeric end of the HLA region resides HLA-DP, a highly polymorphic locus (over 152 unique alleles recognized as of January 2012; http:// www.ebi.ac.uk/imgt/hla/) that is firmly established as a classical transplantation locus [2,3]. Although donor matching is associated with a lower risk of graft-versus-host disease (GVHD), practically, prospective donor matching is difficult because of the weaker linkage disequilibrium that leads to mismatch