Only 30% of subjects needing haematopoetic stem cell transplantation (HSCT) will find HLA identical donors. In the case of related donors, the requirement is to match all 6 alleles at HLA A, B and DRB1, while, for unrelated donors, matching needs to be 8/8, i.e. at HLA A, B, C and DRB1.
An alternative to fully matched donors, is using a haplo-identical donor. This could be a parent, an offspring, a sibling or half-sibling. It is estimated that there is a mean of 2.7 haplo-identical donors available for every subject needing HSCT. These donors are naturally highly motivated, being related donors. Unlike cord blood donations, haplo-identical donors will be available for further infusions of stem cells or lymphocytes at a later date for graft failure or infections respectively if needed.
However, samples of bone marrow or peripheral blood obtained from haplo-identical donors have large numbers of T-cells, giving a much higher risk of GVHD. There is severe bidirectional alloreactivity, also increasing the risk of graft failure. This can be mitigated by depleting the T-lymphocytes in the donor sample with pre-treatment with anti-thymocyte globulin and drugs such as cyclophosphamide or busulfan, and by reducing the risk of GVHD with medthotrexate and cyclosporin or tacrolimus.
Children tend to do better when they receive a haplo-identical graft from the mother rather than the father. Similarly, when receiving the graft from a sibling, they do better if the haplotype mismatch applies to the maternal antigens rather than paternal ones. This is due to the effect of non-inherited maternal antigens (NIMA). It is thought that exposure to maternal antigens in utero, even if those antigens have not been inherited, tolerizes the child's immune system to NIMA. The same does not apply to paternal antigens. Mismatch for paternal antigens carries a worse outcome.
In 2002, Ruggeri and colleagues from Perugia, Italy published a seminal work of research in Science that was to unleash a decade long quest to investigate the role of Natural Killer Cells (NK cells) in transplantation. The role of NK cells, as a part of innate immunity, is to find and destroy cancer cells and infected cells before the adaptive immune system is called into play. They do this by recognising the absence of cognate HLA Class I receptors on the surface of their target cells. If such receptors are detected, the NK cells do not kill them, while if the "self" receptors are absent or not recognised, cytolysis occurs.
To this end, NK cells carry two types of receptors, the NKG2D/CD94 hetero-dimeric receptor which is inhibitory, and a much larger group of receptors called Killer Cell Immunoglobulin-like receptor (KIR), which is comprised of some 15 genes. KIR receptors are broadly of 2 types- A & B. Type A KIR receptors do not have a great deal of antigenic heterogeneity, and are mostly inhibitory. Type B KIR receptors are much more diverse and include both inhibitory and activating receptors. The inhibitory receptors have the suffix L (e.g. KIR2DL. KIR3DL) while activating receptors end with a S (e.g. KIR2DS).
After HSCT, NK cells are usually the first to be repopulated, before T-cells have had time to recover. It is probably stating the obvious to mention that T-cells account for the bulk of graft versus leukaemia (GVL) effect, but increase the risk of GVHD.
Ruggeri and his colleagues found that in T-cell depleted stem cell transplants, when there was mismatch between the recepient's and donor's KIR ligands (the receptors for KIR), GVL effect was better, leukaemia free progression (LFP) was longer and GVHD occurred less often. It is easy to understand why NK cells would attack leukemia cells, but how do you explain a reduced incidence of acute GVHD? It is thought that NK cells do this through allo-reactivity against the recipient's antigen presenting cells (mismatched for KIR ligands).
This effect was not replicated in T-cell replete grafts, presumably because T-cells would increase the risk of GVHD and thus nullify the effect of NK cells.
It is now clear that it is not just the host characteristics that influence graft survival. Unrelated donors who have at least one KIR-B haplotype (KIR B/x, as opposed to KIR A/A), display greater GVL effect, even in T-cell replete grafts. There may therefore be a case or deliberately selecting donors whose NK cells carry KIR-B. KIR-B alleles lying in the centromeric rather than telomeric position appear to provide greater GVL effect. There is also a dose response effect, with greater number of KIR B alleles providing more efficacy.
Further, recipients who are homozygous for HLA-C2 benefit less than those heterozygous or homozygous for HLA-C1. It appears that the activating receptor KIR2DS1, whose cognate receptor is the HLA Class C molecule, will only destroy leukaemia cells that carry HLA-C1, but is tolerized by HLA-C2. Fortunately only 15% of subjects with acute leukaemia are homozygous for HLA-C2.
Finally, mismatch for HLA-Class C antigen between donor and recipient increases the benefits offered by NK cells in terms of GVL effect and LFP through alloreactivity.
It is worth mentioning that these salutary effects of NK cells in haplo-identical and unrelated-donor HSCT are only seen for recipients with AML, but not with ALL.
Hence, if multiple haplo-identical or unrelated, otherwise matched donors are under consideration for a recipient with AML, it is worth selecting the donor with KIR B alleles over a donor who is homozygous for KIR A. There is less agreement over whether to select donors who are deliberately mismatched for KIR ligands to increase NK cell alloreactivity in haploidentical transplants, as some studies have shown a higher risk of GVHD.
References:
1. Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A, Posati S, Rogaia D, Frassoni F, Aversa F, Martelli MF, Velardi A: Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 2002; 295: 2097–2100.
2. Cooley S, Weisdorf DJ, Guethlein LA, Klein JP, Wang T, Le CT, Marsh SG, Geraghty D, Spellman S, Haagenson MD, Ladner M,Trachtenberg E, Parham P, Miller JS: Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia. Blood 2010; 116: 2411–2419.
An alternative to fully matched donors, is using a haplo-identical donor. This could be a parent, an offspring, a sibling or half-sibling. It is estimated that there is a mean of 2.7 haplo-identical donors available for every subject needing HSCT. These donors are naturally highly motivated, being related donors. Unlike cord blood donations, haplo-identical donors will be available for further infusions of stem cells or lymphocytes at a later date for graft failure or infections respectively if needed.
However, samples of bone marrow or peripheral blood obtained from haplo-identical donors have large numbers of T-cells, giving a much higher risk of GVHD. There is severe bidirectional alloreactivity, also increasing the risk of graft failure. This can be mitigated by depleting the T-lymphocytes in the donor sample with pre-treatment with anti-thymocyte globulin and drugs such as cyclophosphamide or busulfan, and by reducing the risk of GVHD with medthotrexate and cyclosporin or tacrolimus.
Children tend to do better when they receive a haplo-identical graft from the mother rather than the father. Similarly, when receiving the graft from a sibling, they do better if the haplotype mismatch applies to the maternal antigens rather than paternal ones. This is due to the effect of non-inherited maternal antigens (NIMA). It is thought that exposure to maternal antigens in utero, even if those antigens have not been inherited, tolerizes the child's immune system to NIMA. The same does not apply to paternal antigens. Mismatch for paternal antigens carries a worse outcome.
In 2002, Ruggeri and colleagues from Perugia, Italy published a seminal work of research in Science that was to unleash a decade long quest to investigate the role of Natural Killer Cells (NK cells) in transplantation. The role of NK cells, as a part of innate immunity, is to find and destroy cancer cells and infected cells before the adaptive immune system is called into play. They do this by recognising the absence of cognate HLA Class I receptors on the surface of their target cells. If such receptors are detected, the NK cells do not kill them, while if the "self" receptors are absent or not recognised, cytolysis occurs.
To this end, NK cells carry two types of receptors, the NKG2D/CD94 hetero-dimeric receptor which is inhibitory, and a much larger group of receptors called Killer Cell Immunoglobulin-like receptor (KIR), which is comprised of some 15 genes. KIR receptors are broadly of 2 types- A & B. Type A KIR receptors do not have a great deal of antigenic heterogeneity, and are mostly inhibitory. Type B KIR receptors are much more diverse and include both inhibitory and activating receptors. The inhibitory receptors have the suffix L (e.g. KIR2DL. KIR3DL) while activating receptors end with a S (e.g. KIR2DS).
After HSCT, NK cells are usually the first to be repopulated, before T-cells have had time to recover. It is probably stating the obvious to mention that T-cells account for the bulk of graft versus leukaemia (GVL) effect, but increase the risk of GVHD.
Ruggeri and his colleagues found that in T-cell depleted stem cell transplants, when there was mismatch between the recepient's and donor's KIR ligands (the receptors for KIR), GVL effect was better, leukaemia free progression (LFP) was longer and GVHD occurred less often. It is easy to understand why NK cells would attack leukemia cells, but how do you explain a reduced incidence of acute GVHD? It is thought that NK cells do this through allo-reactivity against the recipient's antigen presenting cells (mismatched for KIR ligands).
This effect was not replicated in T-cell replete grafts, presumably because T-cells would increase the risk of GVHD and thus nullify the effect of NK cells.
It is now clear that it is not just the host characteristics that influence graft survival. Unrelated donors who have at least one KIR-B haplotype (KIR B/x, as opposed to KIR A/A), display greater GVL effect, even in T-cell replete grafts. There may therefore be a case or deliberately selecting donors whose NK cells carry KIR-B. KIR-B alleles lying in the centromeric rather than telomeric position appear to provide greater GVL effect. There is also a dose response effect, with greater number of KIR B alleles providing more efficacy.
Further, recipients who are homozygous for HLA-C2 benefit less than those heterozygous or homozygous for HLA-C1. It appears that the activating receptor KIR2DS1, whose cognate receptor is the HLA Class C molecule, will only destroy leukaemia cells that carry HLA-C1, but is tolerized by HLA-C2. Fortunately only 15% of subjects with acute leukaemia are homozygous for HLA-C2.
Finally, mismatch for HLA-Class C antigen between donor and recipient increases the benefits offered by NK cells in terms of GVL effect and LFP through alloreactivity.
It is worth mentioning that these salutary effects of NK cells in haplo-identical and unrelated-donor HSCT are only seen for recipients with AML, but not with ALL.
Hence, if multiple haplo-identical or unrelated, otherwise matched donors are under consideration for a recipient with AML, it is worth selecting the donor with KIR B alleles over a donor who is homozygous for KIR A. There is less agreement over whether to select donors who are deliberately mismatched for KIR ligands to increase NK cell alloreactivity in haploidentical transplants, as some studies have shown a higher risk of GVHD.
References:
1. Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A, Posati S, Rogaia D, Frassoni F, Aversa F, Martelli MF, Velardi A: Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 2002; 295: 2097–2100.
2. Cooley S, Weisdorf DJ, Guethlein LA, Klein JP, Wang T, Le CT, Marsh SG, Geraghty D, Spellman S, Haagenson MD, Ladner M,Trachtenberg E, Parham P, Miller JS: Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia. Blood 2010; 116: 2411–2419.
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