scholarly journals Haploidentical hematopoietic transplantation for the cure of leukemia: from its biology to clinical translation

Blood ◽  
2016 ◽  
Vol 128 (23) ◽  
pp. 2616-2623 ◽  
Author(s):  
Antonella Mancusi ◽  
Loredana Ruggeri ◽  
Andrea Velardi
Keyword(s):  
T Cell ◽  
Ex Vivo ◽  
Killer Cell ◽  
Human Leukocyte ◽  
Leukocyte Antigen ◽  
Graft Versus Host ◽  
Haploidentical Transplantation ◽  
Hematopoietic Transplantation ◽  
Human Leukocyte Antigen Haplotype ◽  
Mother To Child

Abstract The present review describes the biology of human leukocyte antigen haplotype mismatched (“haploidentical”) transplantation, its translation to clinical practice to cure leukemia, and the results of current transplantation protocols. The 1990s saw what had been major drawbacks of haploidentical transplantation, ie, very strong host-versus-graft and graft-versus-host alloresponses, which led respectively to rejection and graft-versus-host disease (GVHD), being overcome through transplantation of a “mega-dose” of T cell–depleted peripheral blood hematopoietic progenitor cells and no posttransplant pharmacologic immunosuppression. The absence of posttransplant immunosuppression was an opportunity to discover natural killer cell alloreactions that eradicated acute myeloid leukemia and improved survival. Furthermore, it also unveiled the benefits of transplantation from mother donors, a likely consequence of the mother-to-child interaction during pregnancy. More recent transplantation protocols use unmanipulated (without ex vivo T-cell depletion) haploidentical grafts combined with enhanced posttransplant immunosuppression to help prevent GVHD. Unmanipulated grafts substantially extended the use of haploidentical transplantation with results than even rival those of matched hematopoietic transplantation. In T cell–depleted haploidentical transplantation, recent advances were made by the adoptive transfer of regulatory and conventional T cells.

Mother Donors Confer Protection Against Infectious Mortality after Haploidentical T Cell-Depleted Hematopoietic Transplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2485-2485
Author(s):  
Loredana Ruggeri ◽  
Antonella Tosti ◽  
Antonella Mancusi ◽  
Fabiana Topini ◽  
Elena Urbani ◽  
...  
Keyword(s):  
T Cell ◽  
Conflicts Of Interest ◽  
Hla Antigens ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Histocompatibility Antigens ◽  
Haploidentical Transplantation ◽  
Cell Clones ◽  
Hematopoietic Transplantation ◽  
Mother To Child

Abstract Transplacental trafficking of maternal and fetal cells during pregnancy establishes long-term, reciprocal microchimerism in both mother and child because of exposure of the two immune systems to the non-self alloantigens (Maloney et al., J Clin Invest. 1999;104:41-47). Studies show the immune system in the mother is capable of being sensitized by paternal histocompatibility antigens. For example, antibodies directed against paternal HLA-antigens (van Rood et al., Nature. 1958;181:1735-1736) and T lymphocytes directed against paternal major (van Kampen et al., Hum Immunol. 2001;62:201-207) and minor histocompatibility antigens (Verdijk et al., Blood. 2004;103:1961-1964) are frequently detected in multiparous women. We previously demonstrated mother/child immune interactions positively influenced the outcome of mother to child HLA haploidentical T cell-depleted hematopoietic transplantation. In a series of adult and pediatric patients we demonstrated mother donors conferred protection against leukemia relapse and improved transplant related mortality (TRM), which was largely due to infection, and improved survival (Stern et al., Blood 2008, Oct 1;112:2990-5). However, in unmanipulated haploidentical transplantation, it has been recently shown that transplantation from mother donors increases the incidence of GvHD and decreases survival (Huang et al., EBMT 2014). Here, we analyzed the outcomes of 238 adult acute leukemia patients after T cell-depleted haploidentical transplantation. When compared with transplantation from all other family members, transplantation from mother donors was associated with significantly lower TRM (largely infectious) (27% vs 50% from all other donors, P = 0.01). Multivariate analyses demonstrated transplantation from mother donors was an independent factor predicting improved survival (hazard ratio 0.41, 95% confidence interval 0.12 to 0.95, P = 0.03). In an attempt to elucidate the mechanism, we analyzed donor T cell repertoires that were specific for CMV antigens presented by recipient APCs (by ELISPOT and by limiting dilution cloning). Unlike all other donor/recipient pairs, mothers possessed CMV-specific CD8 cell clones that killed child’s and father’s CMV-pulsed dendritic cells (DCs). Such clones were non-alloreactive as they did not kill the child’s or father’s non-CMV-pulsed DCs. Mothers also possessed CD4 T cell clones that produced IFN-gamma in response to child’s and father’s CMV-loaded antigen-presenting cells (APCs). Such clones were non-alloreactive as they did not respond to child’s or father’s non-CMV-pulsed APCs. Thus, mothers possessed a T cell repertoire that recognized CMV antigens also when presented by the unshared, father’s, HLA haplotype. In fact, they showed twice as many T cells that recognized CMV antigens presented by the child’s APCs than all other donor/recipient pairs (p<0.05). Apparently, therefore, pregnancy resulted in the generation of an additional T cell repertoire that specifically recognized pathogen antigens presented by the unshared paternal HLA haplotype antigens on the child’s APCs. Apparently, upon mother to child T cell-depleted hematopoietic transplantation, such repertoire expands over time and helps reduce infectious mortality. Further studies are needed to elucidate the mechanisms underlying mother T cell selection/education by paternal HLA haplotype antigens on the child’s APCs. Disclosures No relevant conflicts of interest to declare.

Postgrafting administration of granulocyte colony-stimulating factor impairs functional immune recovery in recipients of human leukocyte antigen haplotype–mismatched hematopoietic transplants

Blood ◽  
2001 ◽  
Vol 97 (8) ◽  
pp. 2514-2521 ◽  
Author(s):  
Isabella Volpi ◽  
Katia Perruccio ◽  
Antonella Tosti ◽  
Marusca Capanni ◽  
Loredana Ruggeri ◽  
...  
Keyword(s):  
T Cell ◽  
Human Leukocyte ◽  
Immune Reactivity ◽  
Immune Recovery ◽  
Cd4 Cells ◽  
Cell Reactivity ◽  
Leukocyte Antigen ◽  
Human Leukocyte Antigen Haplotype ◽  
T Cell Reactivity ◽  
Stimulating Factor

Abstract In human leukocyte antigen haplotype–mismatched transplantation, extensive T-cell depletion prevents graft-versus-host disease (GVHD) but delays immune recovery. Granulocyte colony-stimulating factor (G-CSF) is given to donors to mobilize stem cells and to recipients to ensure engraftment. Studies have shown that G-CSF promotes T-helper (Th)-2 immune deviation which, unlike Th1 responses, does not protect against intracellular pathogens and fungi. The effect of administration of G-CSF to recipients of mismatched hematopoietic transplants with respect to transplantation outcome and functional immune recovery was investigated. In 43 patients with acute leukemia who received G-CSF after transplantation, the engraftment rate was 95%. However, the patients had a long-lasting type 2 immune reactivity, ie, Th2-inducing dendritic cells not producing interleukin 12 (IL-12) and high frequencies of IL-4– and IL-10–producing CD4+ cells not expressing the IL-12 receptor β2 chain. Similar immune reactivity patterns were observed on exposure of donor cells to G-CSF. Elimination of postgrafting administration of G-CSF in a subsequent series of 36 patients with acute leukemia, while not adversely affecting engraftment rate (93%), resulted in the anticipated appearance of IL-12–producing dendritic cells (1-3 months after transplantation versus &gt; 12 months in transplant recipients given G-CSF), of CD4+ cells of a mixed Th0/Th1 phenotype, and of antifungal T-cell reactivity in vitro. Moreover, CD4+ cell counts increased in significantly less time. Finally, elimination of G-CSF–mediated immune suppression did not significantly increase the incidence of GVHD (&lt; 15%). Thus, this study found that administration of G-CSF to recipients of T-cell–depleted hematopoietic transplants was associated with abnormal antigen-presenting cell functions and T-cell reactivity. Elimination of postgrafting administration of G-CSF prevented immune dysregulation and accelerated functional immune recovery.

scholarly journals Leukemia-associated minor histocompatibility antigen discovery using T-cell clones isolated by in vitro stimulation of naive CD8+ T cells

Blood ◽  
2010 ◽  
Vol 115 (23) ◽  
pp. 4923-4933 ◽  
Author(s):  
Marie Bleakley ◽  
Brith E. Otterud ◽  
Julia L. Richardt ◽  
Audrey D. Mollerup ◽  
Michael Hudecek ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Human Leukocyte Antigen ◽  
T Lymphocyte ◽  
Graft Versus Host Disease ◽  
Cytotoxic T Lymphocyte ◽  
Human Leukocyte ◽  
Leukocyte Antigen ◽  
Graft Versus Host

Abstract T-cell immunotherapy that targets minor histocompatibility (H) antigens presented selectively by recipient hematopoietic cells, including leukemia, could prevent and treat leukemic relapse after hematopoietic cell transplantation without causing graft-versus-host disease. To provide immunotherapy that can be applied to a majority of transplantation recipients, it is necessary to identify leukemia-associated minor H antigens that result from gene polymorphisms that are balanced in the population and presented by common human leukocyte antigen alleles. Current approaches for deriving minor H antigen–specific T cells, which provide essential reagents for the molecular identification and characterization of the polymorphic genes that encode the antigens, rely on in vivo priming and are often unsuccessful. We show that minor H antigen–specific cytotoxic T lymphocyte precursors are found predominantly in the naive CD8+ T-cell subset and provide an efficient strategy for in vitro priming of native T cells to generate T cells to a broad diversity of minor H antigens presented with common human leukocyte antigen alleles. We used this approach to derive a panel of stable cytotoxic T lymphocyte clones for discovery of genes that encode minor H antigens and identify a novel antigen expressed on acute myeloid leukemia stem cells and minimally in graft-versus-host disease target tissues.

Comparable Immune Reconstitution Achieved Following Unmanipulated HLA-Mismatched/Haploidentical Transplantation and HLA-Identical Sibling Transplantation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2312-2312
Author(s):  
Ying-Jun Chang ◽  
Xiao Jun Huang ◽  
Xiang-Yu Zhao ◽  
Ming-Rui Huo ◽  
Lan-Ping Xu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Human Leukocyte ◽  
Cd4 T Cell ◽  
Transplant Recipients ◽  
Leukocyte Antigen ◽  
Haploidentical Transplantation ◽  
Cell Counts ◽  
Time Point

Abstract Abstract 2312 Unmanipulated human leukocyte antigen (HLA)-mismatched/haploidentical trasnplantation is an established treatment for patients without HLA-matched related or unrelated donors. In contrast to HLA-matched transplant, intensified immnological suppression, including antithymocyte globulin was used to overcome the HLA barrier. However, it is currently unclear how this radically different transplantation strategy affect immunological recovery. To investigate the immune reconstituion following unmanipulated human leukocyte antigen (HLA)-mismatched/haploidentical trasnplantation and HLA-matched transplantation. Seventy-five patients underwent transplantation from either HLA-identical siblings (25 cases) or haploidentical donors (50 cases) were enrolled in this prospective study. Recovery of T-, B-, monocytes, and dendritic cell subsets, proliferative of T lymphocytes in vitro response to mitogens, were investigated. Our results showed that in the first 90 days after grafting, counts of the following T cell subsets were signifcantly lower in haploidentical transplant recipients than those of HLA-matched transplant recipients: total CD4+ T cells, and their CD45RA positive (naïve), CD45RO (memory) subpopulation. After this interval, increases in CD4+, CD4+ naïve, and CD4+ memory T cell counts were observed in surviving subjects, by 1 year after transplantation, there were no differences in the numbers of recovered CD4+, CD4+ naïve, and CD4+ memory T cells between patients receiving haploidentical transplant and those receiving HLA-identical transplantation. In contrast, total counts of CD8+ T cells declined after conditioning and were significantly reduced by day 30 post-haploidentical transplantation. Thereafter, absolute of CD8+ T cell numbers expanded dramatically, and were signifciantly higher than that of HLA-identical recipients since day 90 post transplantation time point (Figure). CD3+ cells, CD8+ naïve, and CD8+ memory T cells were comparable by 90 days after transplantation, although lower numbers of these cells were found in haploidentical group prior day 90 after grafting. Furthermore, the ratio of CD4/CD8 T cells was significantly inverted in both groups untill 1 year after transplantation. While monocytes recovered promptly and reached normal levels by day 15 after haploidentical transplantation, though they also declined slightly by the 1 year time point, at which CD4+ T cell counts rebounded. These results indciate that quantitative CD4+ T-cell recovery is delayed after haploidentical transplantation, they also suggest that compensatory expansion of cytotoxic T lymphocytes and monocytes may accompany CD4+ T lymphopenia. Subsets of DC, including myeloid DC 1 (MDC1), MDC2 and plasmacytoid DC (pDC), in haploidentical recipients on day 15, and day 30 post allografting were significantly lower than those in HLA-matched recipients. No sigificant difference in the counts of B cells at any time point after transplantation in haploidentical recipients and HLA-matched recipients were found. On day 15 after transplantation, the expression of CD28 on CD8+ T cells was sigificantly lower in patients receiving haploidentical transplantation, then increased promptly and signifcantly higher than those receiving HLA-matched transplant on day 30, and 90, after this two time point the expression of CD28 were comparable between two groups. Moreover, the expression of CD28 on CD4+ T cells was also signifcantly higher than those receiving HLA-matched transplant on day 30, and 90. While only at days 30 post transplant, the expession of CD80 on pDC were signifcantly higher in patients receiving haploidentical transplant and than those receiving HLA-identical transplantation. The ability of the patient-derived T cells to produce IFN-Ã and IL-4 by day 30 after transplantation was similar in in patients without aGVHD between haploidentical transplant recipients and HLA-matched recipients. Our results suggest that comparable immune reconstitution could be achieved folloing hapolidentical transplantation and HLA-matched transplantation, this is related to the similar transplant outcomes. Fig The capability of T cells to produce IFN-Ã and IL-4 in patients without aGVHD between HLA-matched transplantation (the former box) and haploidentical transplantation (the latter box). Fig. The capability of T cells to produce IFN-Ã and IL-4 in patients without aGVHD between HLA-matched transplantation (the former box) and haploidentical transplantation (the latter box). Disclosures: No relevant conflicts of interest to declare.

Primary cutaneous CD8+ and CD56+ T-cell lymphomas express HLA-G and killer-cell inhibitory ligand, ILT2

Blood ◽  
2004 ◽  
Vol 103 (5) ◽  
pp. 1796-1798 ◽  
Author(s):  
Mirjana Urosevic ◽  
Jivko Kamarashev ◽  
Günter Burg ◽  
Reinhard Dummer
Keyword(s):  
T Cell ◽  
Clinical Course ◽  
Killer Cell ◽  
Human Leukocyte ◽  
Interleukin 10 ◽  
Leukocyte Antigen ◽  
T Cell Lymphomas ◽  
Cutaneous Lymphomas ◽  
Aggressive Clinical Course ◽  
Human Leukocyte Antigen G

Abstract Primary cutaneous lymphomas constitute a spectrum of diseases characterized by a clonal accumulation of lymphocytes in the skin. Cutaneous T-cell lymphomas of the cytotoxic phenotype, including CD8+ and CD56+ lymphomas, are rare entities that have only been recently recognized and characterized. These lymphomas often show an aggressive clinical course. We investigated the expression of human leukocyte antigen G (HLA-G) and interleukin 10 (IL-10) in conjunction with expression of HLA-G killer-cell inhibitory receptor ligand immunoglobulin-like transcript 2 (ILT2) in 3 CD56+CD4+ and 4 CD8+ cutaneous T-cell lymphomas. HLA-G expression was detected in 2 of 3 lymphomas of the CD56+CD4+ type and in all lymphomas of CD8+ type. It is of note that CD56+CD4+ lymphomas displayed stronger HLA-G reactivity. The expression of IL-10 matched the expression of HLA-G. Together with the expression of IL-10, HLA-G might be one of the factors accounting for the evasion of immunosurveillance, thus contributing to aggressive phenotype of these lymphoma entities.

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