Cytomegalovirus (CMV) Reactivation after T-Cell Replete Reduced-Intensity Conditioning (RIC) Allogeneic Hematopoietic Stem Cell Transplantation (AHSCT) Correlates with Donor KIR Genotype.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2974-2974
Author(s):  
Ronald Sobecks ◽  
Medhat Askar ◽  
Dawn Thomas ◽  
Lisa Rybicki ◽  
Matt Kalaycio ◽  
...  
Keyword(s):  
T Cell ◽  
Multivariable Analysis ◽  
Hla Class I ◽  
Hematopoietic Stem ◽  
Kir Genes ◽  
Sibling Donor ◽  
Hla Class I Molecules ◽  
Matched Sibling ◽  
Cmv Reactivation ◽  
Kir Genotypes

Abstract CMV remains the most common viral infection after AHSCT. NK and T cells provide protection against CMV reactivation. The interaction of inhibitory killer immunoglobulin-like receptors (KIRs) with target cell HLA class I molecules regulates NK cells and some T cell populations. Donor activating KIR genotype has been suggested to influence CMV reactivation after myeloablative AHSCT (Cook et al, Blood2006;107:1230–1232). However, the effect of donor activating or inhibitory KIR genotype on CMV reactivation after T-cell replete RIC AHSCT has not been reported. We analyzed 64 consecutive patients (pts) who underwent T-cell replete matched sibling donor RIC AHSCT at our institution from 1/16/00-4/24/07 with fludarabine and low-dose total body irradiation (200 cGy: 36 pts; 400 cGy: 28 pts). All pts received cyclosporine and mycophenolate mofetil for GVHD prophylaxis. CMV monitoring was performed by polymerase chain reaction testing. 49 (77%) pts were CMV seropositive or had a CMV seropositive donor; 25/49 (51%) had CMV reactivation post-AHSCT. 15 (23%) pts were CMV seronegative along with their donors and 1 (7%) of them had CMV reactivation. Donor activating KIR genotypes (KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, KIR2DS5, KIR3DS1) and inhibitory genotypes (KIR2DL1, KIR2DL2, KIR2DL3, KIR3DL1, KIR3DL2) were determined by PCR-SSOP and/or PCR-SSP. Patient HLA KIR ligands including HLA-Cw groups C1 or C2, HLA-Bw4 and HLA-A3/11 (reviewed in Farag et al Blood2002; 100:1935–1947) and donor inhibitory KIR genotypes were analyzed. Missing patient KIR ligand was observed in 15 (23%) of the C1 group, 27 (42%) of the C2 group, 25 (39%) of the HLA-Bw4+ pts and 43 (67%) of the HLA-A3/11+ pts. There were no differences observed for CMV reactivation between any of these groups when comparing those with or without missing ligands. However, when the number of donor activating KIRs were considered a difference in CMV reactivation patterns was appreciated. Pts whose donor KIR genotype contained 5 or 6 activating KIR genes (N=16) had less CMV reactivation compared to those with only 1 to 4 activating KIR genes (N=48) (19% vs. 48%). This finding remained significant on multivariable analysis (p=0.038). No specific activating KIR was found to be associated with CMV reactivation. There were no differences between the groups (5–6 vs. 1–4 activating KIR genes) with regards to patient/donor CMV seropositivity, age, diagnoses, gender, race, number of prior chemotherapy regimens, prior radiation, time from diagnosis to RIC AHSCT, TBI dose, donor to patient gender, CD34+ and CD3+ cell doses. We conclude that donor activating KIR genotype influences CMV reactivation after matched sibling donor T-cell replete RIC AHSCT. These results may guide the selection of donors as well as identify patients who may benefit from closer CMV monitoring and additional strategies to prevent CMV reactivation post transplant. Figure Figure

scholarly journals NK cells expressing inhibitory KIR for non–self-ligands remain tolerant in HLA-matched sibling stem cell transplantation

Blood ◽  
2010 ◽  
Vol 115 (13) ◽  
pp. 2686-2694 ◽  
Author(s):  
Andreas T. Björklund ◽  
Marie Schaffer ◽  
Cyril Fauriat ◽  
Olle Ringdén ◽  
Mats Remberger ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Nk Cells ◽  
Cell Transplantation ◽  
Nk Cell ◽  
Hla Class I ◽  
Class I ◽  
Hematopoietic Stem ◽  
Matched Sibling

Abstract Natural killer (NK)–cell alloreactivity in recipients of hematopoietic stem cell grafts from HLA-identical siblings is intriguing and has suggested breaking of NK-cell tolerance during the posttransplantation period. To examine this possibility, we analyzed clinical outcomes in a cohort of 105 patients with myeloid malignancies who received T cell–replete grafts from HLA-matched sibling donors. Presence of inhibitory killer cell immunoglobulin-like receptors (KIRs) for nonself HLA class I ligands had no effect on disease-free survival, incidence of relapse, or graft-versus-host disease. A longitudinal analysis of the NK-cell repertoire and function revealed a global hyporesponsiveness of NK cells early after transplantation. Functional responses recovered at approximately 6 months after transplantation. Importantly, NKG2A− NK cells expressing KIRs for nonself HLA class I ligands remained tolerant at all time points. Furthermore, a direct comparison of NK-cell reconstitution in T cell–replete and T cell–depleted HLA-matched sibling stem cell transplantation (SCT) revealed that NKG2A+ NK cells dominated the functional repertoire early after transplantation, with intact tolerance of NKG2A− NK cells expressing KIRs for nonself ligands in both settings. Our results provide evidence against the emergence of alloreactive NK cells in HLA-identical allogeneic SCT.

Influence of Killer Immunoglobulin-Like Receptor (KIR) Matching on Achieving T Cell (CD3+) Complete Donor Chimerism (CDC) in Related Donor Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation (NMHSCT).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3012-3012
Author(s):  
Ronald Sobecks ◽  
Edward J. Ball ◽  
Medhat Askar ◽  
Karl Theil ◽  
Lisa Rybicki ◽  
...  
Keyword(s):  
T Cell ◽  
Nk Cells ◽  
Donor Cell ◽  
Hla Class I ◽  
Cellular Level ◽  
T Cell Subsets ◽  
Hematopoietic Stem ◽  
Effector Cells ◽  
Hla Class I Molecules ◽  
Related Donor

Abstract The reactivity of NK cells and some T cell populations is regulated by KIR interactions with HLA class I molecules. Such interactions have been suggested to influence outcomes after myeloablative allogeneic HSCT. However, in NMHSCT the effect of KIR interactions on outcomes including the development of CDC has not been well described. We analyzed 51 pts who received related donor NMHSCT at our institution from 1/10/00–10/25/05. All pts received fludarabine 30 mg/m2/d x 3 days followed by total body irradiation 200 cGy (n=35) or 400 cGy (n=16) for conditioning. The median age was 54 (range, 21–64). Short tandem repeat analysis for T cell (CD3+) chimerism was performed on peripheral blood and CDC was defined as achievement of >95% DNA of donor origin in the CD3+ T cells. 37 (73%) of patients achieved CDC at a median time of 3.3 mos (range, 0.4–11.2). KIR genotypes were determined for recipients by PCR-rSSOP analysis. Donor HLA KIR ligands were categorized as: HLA-Cw groups C1 (+ or −); C2 (+ or −); HLA-Bw4 (+ or −); and HLA-A3 or -A11 (+ or −) [as reviewed by Farag et al. Blood2002; 100:1935–47]. Recipient KIR genotype and donor HLA KIR ligands were used to generate an inhibitory KIR score for pts from 1 to 4 corresponding to the potential number of inhibitory KIRs engaged. 7 pts had a score of 1, 27 had a score of 2, 14 had a score of 3 and 3 had a score of 4. Figure Figure The Kaplan-Meier method was used to estimate the achievement of CDC by inhibitory KIR score (figure, p=0.09). Pts with a score of 1 were less likely to achieve CDC compared to those with a score of 2 (p=0.02), while those with a score of 2 tended to be less likely to develop CDC than those with a score of 4 (p=0.07). There were no differences in CD34+ or CD3+ cell doses between any of the groups. When combined with the inhibitory KIR score data the presence of single or multiple activating KIR’s was not found to influence the development of CDC. Thus, pts with lower inhibitory KIR scores may have more active anti-donor effector cells (NK cells and T cell subsets) that may reduce donor cell chimerism. Conversely, those with higher inhibitory KIR scores may have less active populations and be more likely to achieve CDC. Given the genotypic potential to inhibit all NK cells KIR expression may be variable among different clones, and may affect the development of CDC. Further investigation of KIR expression at the cellular level rather than by genotyping alone should be pursued.

The Presence and Number of Activatory KIR (R+D−) Impact the Infection and Survival Status of Patients Transplanted with an HLA Matched Sibling Donor.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3339-3339
Author(s):  
Pascale Loiseau ◽  
Chun Chen ◽  
Marie-Lorraine Appert ◽  
Vanderson Rocha ◽  
Marc Busson ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Fungal Infections ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Survival Status ◽  
Kir Genes ◽  
Sibling Donor ◽  
Recipient Age ◽  
Matched Sibling ◽  
Group 2

Abstract Killer immunoglobulin-like receptor (KIR) ligand incompatibilities (=absence on recipient tissues of a ligand for KIRs present in the graft) have been associated with decreased relapse, rejection and acute GVHD, after T cell depleted haplo and unrelated donor Hematopoietic Stem cell transplantation, mainly for myeloid hematopoietic malignancies. The association of donor and recipient KIR genotypes with outcomes, including infections, after HLA genoidentical HSCT has not been studied. We have analysed genotypes for ten KIR genes (2DS1, 2DS2, 2DS3, 2DS4, 2DL1, 2DL2, 2DL3, 3DS1, 3DL1, 3DL2) in 131 donor-recipient pairs from HLA-matched sibling bone marrow transplantations performed for lymphoid (53 cases) and for myeloid malignant diseases (78 cases). We classified the pairs according to KIR-ligand incompatibilities and donor-recipient KIR matching (=concommitant expression of KIRs in donors and recipients). Median age was 29 years. 105 patients were transplanted for a low risk disease, 12 for intermdiate and 14 for high risk disease. Conditioning was myeloablative in all cases and consisted in TBI based (n=63). Cyclosporine and Methotrexate for GVHD prophylaxis was used in 118 cases. Cumulative incidence (competing rsik analysis) of acute GVHD at day 100 and CI of 180 days-bacterial, CMV and fungal infections were 48%, 19%, 34%, 11%, respectively. 5 years overall survival was 70%. We have not found any significant association of “KIR-ligand incompatibilities”, donor KIR genotype, number of activatory KIR genes present in the donor and donor-recipient matching for each KIR with aGVHD, relapse, bacterial, viral or fungal infection and survival, except for KIR2DS2. In fact, donor-recipient mismatching for KIR2DS2 was associated with the incidence of acute GVHD (II-IV p=0.05). Although not significant, we have also observed a trend with decreased survival in patients homozygous for group 2 HLA-C and grafted for myeloid malignant disease with a HLA-matched sibling donor carrying the activatory KIR2DS2 (63 % survival at 20 months (N=6) versus 86% (N=9)). Finally,. the higher is the number of activatory KIRs present in the recipient (R+) and absent from the donor (D−), the higher is the risk of fungal (p=0.03) and CMV infection (p=0.05) and the worse is the survival (at 5 years: 78% survival in case of 0 KIR R+D−, 64% in case of 1 or 2 KIR R+D− and 44% in case of 3 or 4 KIR R+D−, p=0.001). A multivariate analysis for survival confirmed the association of number of R+D− activatory KIR (p = 0.001, HR = 3.13) among other clinical factors such as gender (p=0.03), ABO compatibility (p=0.003), recipient age (p=0.01) and status of the disease (p = 0.0001).

scholarly journals Characterisation of B killer cell immunoglobulin-like receptor genes and telomeric and centromeric motifs in hematopoietic stem cell transplantation donors in Vojvodina, Serbia

Genetika ◽  
2017 ◽  
Vol 49 (1) ◽  
pp. 345-354
Author(s):  
Dusica Ademovic-Sazdanic ◽  
Svetlana Vojvodic ◽  
S. Popovic ◽  
N. Konstantinidis
Keyword(s):  
Relapse Prevention ◽  
Hematological Malignancies ◽  
Killer Cell ◽  
Simple Algorithm ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Kir Genes ◽  
Graft Versus Leukemia ◽  
Kir Gene ◽  
Kir Genotypes

The outcome of HSCT is strongly in?uenced by the genetic similarity or identity in the HLA genes that affects the incidence of graft-versus-host disease (GvHD). Successful allogeneic HSCT, however, depends also on T-cell mediated graft-versus-leukemia (GvL) effect, in which donor-derived T cells and natural killer (NK) cells kill these malignant cells in the patient, therefore playing a crucial role in relapse prevention. The aim of this study was to make the predictive analysis of the structure and distribution of B KIR alleles and centromeric and telomeric KIR genotypes in HSCT donors in Vojvodina with regard to their contribution to protection from relapse. A total of 124 first-degree relatives of patients with hematological malignancies were examined for the presence or absence of 15 KIR genes by using of PCR-SSO technique with Luminex xMap technology. The percentage of individuals carrying each KIR gene, centromeric and telomeric KIR haplotypes and genotypes was determined by direct counting. Sixty two percent of the HSCT donors in Vojvodina carry A KIR haplotype, while nearly 38% carry B KIR haplotype. The distribution of B KIR genes showed that among 124 studied HSCT donors, 31(25%) do not carry none of the KIR genes belonging to B group, 71.77% of donors have two or more B KIR genes, 61.29% of them carry KIR 2DL2 and 2DS2 or more B KIR genes. The analysis of centromeric and telomeric KIR genotypes, showed that Cen-A1/Tel-A1 genotype had a highest frequency of 51.47% and Cen-B2/Tel-B1 the lowest frequency of 1.30%. The usage of donor KIR B gene content and centromeric and telomeric KIR gene structure could be used in development of a simple algorithm to identify donors who will provide the most protection against the relapse in related HSC transplants.

scholarly journals T-cell malignancies with mature phenotypes: altered cell cycle regulation by HLA class I molecules

Blood ◽  
1991 ◽  
Vol 78 (8) ◽  
pp. 2045-2052 ◽  
Author(s):  
MC Turco ◽  
F Alfinito ◽  
M De Felice ◽  
A Lamberti ◽  
S Ferrone ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Dna Synthesis ◽  
Hla Class I ◽  
Class I ◽  
Mitogenic Effect ◽  
Prolymphocytic Leukemia ◽  
T Lymphocyte Proliferation ◽  
Hla Class I Molecules

Abstract Soluble anti-HLA class I monoclonal antibodies (MoAbs) modulate normal T-lymphocyte proliferation induced via the CD3/Ti and the CD2 pathway, but do not induce proliferation of normal T lymphocytes in the absence of additional mitogenic stimuli. In this report, we show that anti-HLA class I MoAbs induce DNA synthesis in peripheral blood mononuclear cells from a patient with a CD4+CD8+T-prolymphocytic leukemia (T-PLL) and from a patient with a CD4-CD8+ T-chronic lymphocytic leukemia (T- CLL), in the absence of detectable additional mitogenic stimuli. Proliferation of leukemic T cells is induced by both whole Igs and Fab' fragments of anti-HLA class I MoAbs, arguing in favor of their direct interactions with the proliferating cells as the mechanism underlying the mitogenic effect. This interpretation is also supported by the ability of anti-HLA class I MoAbs to induce proliferation of leukemic T- cell preparations, depleted of accessory cells. DNA synthesis in T-CLL and T-PLL cells is preceded by expression of G1-specific messenger RNAs, ie. c-myc, 2F1, Tac, and interferon-gamma, in activated cells. Cell proliferation is inhibited by the protein kinase C inhibitor H7, indicating that activation of this enzyme is required for the mitogenic effect of anti-HLA class I MoAbs. The latter inhibit the proliferation of T-CLL cells as well as that of normal T cells stimulated with anti- CD3 MoAbs and enhance that of both types of cells stimulated with anti- CD2 MoAbs. In addition, anti-HLA class I MoAb Q6/64 in combination with anti-CD2 MoAb 9.6 or MoAb 9–1 induces proliferation of leukemic T cells to a greater extent than the individual MoAbs, but is not mitogenic for normal T cells. Anti-HLA class I MoAbs restore the cytolytic activity of T-CLL cells that is lost after 5 days of incubation of control medium, suggesting that HLA class I antigens may mediate a signal contributing to the activation state. The present results indicate that leukemic T-cell proliferation can be triggered via HLA class I molecules and suggest a potential role for these antigens in the in vivo growth of malignant clones.

scholarly journals Fas-Independent Apoptosis of Activated T Cells Induced by Antibodies to the HLA Class I α1 Domain

Blood ◽  
1997 ◽  
Vol 90 (9) ◽  
pp. 3629-3639 ◽  
Author(s):  
Laurent Genestier ◽  
Romain Paillot ◽  
Nathalie Bonnefoy-Berard ◽  
Geneviéve Meffre ◽  
Monique Flacher ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Heavy Chain ◽  
Hla Class I ◽  
Class I ◽  
T Cell Proliferation ◽  
Activated T Cells ◽  
Hla Class I Molecules

Abstract In addition to their major function in antigen presentation and natural killer cell activity regulation, HLA class I molecules may modulate T-cell activation and proliferation. Monoclonal antibodies (MoAbs) that recognize distinct epitopes of HLA class I molecules were reported to interfere with T-cell proliferation. We show here that two MoAbs (mouse MoAb90 and rat YTH862) that bind to an epitope of the α1 domain of HLA class I heavy chain induce apoptotic cell death of activated, but not resting, peripheral T lymphocytes. Other reference anti-HLA class I antibodies specific for distinct epitopes of the α1 (B9.12.1), α2 (W6/32), or α3 (TP25.99) domains of the heavy chain decreased T-cell proliferation but had little or no apoptotic effect. Apoptosis shown by DNA fragmentation, phosphatidylserine externalization, and decrease of mitochondrial transmembrane potential was observed whatever the type of T-cell activator. Apoptosis did not result from Fas/Fas-L interaction and distinct though partly overlapping populations of activated T cells were susceptible to Fas– and HLA class I–mediated apoptosis, respectively. Induction of apoptosis did not require HLA class I cross-linking inasmuch as it could be observed with monovalent Fab′ fragments. The data indicate that MoAb90 and YTH862 directed against the α1 domain of HLA class I trigger apoptosis of activated T lymphocytes by a pathway which does not involve Fas-ligand.

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