scholarly journals Identification of phosphatidylinositol 4-kinase type II   as HLA class II-restricted target in graft versus leukemia reactivity

2008 ◽  
Vol 105 (10) ◽  
pp. 3837-3842 ◽  
Author(s):  
M. Griffioen ◽  
E. D. van der Meijden ◽  
E. H. Slager ◽  
M. W. Honders ◽  
C. E. Rutten ◽  
...  
Keyword(s):  
Class Ii ◽  
Hla Class Ii ◽  
Type Ii ◽  
Graft Versus Leukemia ◽  
Phosphatidylinositol 4

Identification of Phosphatidylinositol 4-Kinase Type II β as the First HLA Class II Associated Minor Histocompatibility Antigen Involved in Graft Versus Leukemia Reactivity.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1800-1800
Author(s):  
Marieke Griffioen ◽  
Edith D. van der Meijden ◽  
M. Willy Honders ◽  
Caroline Rutten ◽  
Simone A.P. van Luxemburg-Heijs ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Class Ii ◽  
Hla Class Ii ◽  
Type Ii ◽  
Cell Therapies ◽  
Graft Versus Leukemia ◽  
Hla Dq ◽  
Phosphatidylinositol 4

Abstract Patients with hematological malignancies can be successfully treated with HLA-matched T cell-depleted allogeneic stem cell transplantation (alloSCT) and subsequent donor lymphocyte infusions (DLI). The efficacy of DLI is mediated by donor T cells recognizing minor histocompatibility antigens (mHags) on malignant recipient cells. Since HLA class II molecules are predominantly expressed on hematopoietic cells, mHag specific CD4+ T cells may selectively mediate Graft-versus-Leukemia (GvL) reactivity without Graft-versus-Host Disease (GvHD). Clinical studies have shown that adoptive transfer of CD4+ donor lymphocytes after HLA-matched alloSCT may lead to clinical remissions with a reduced incidence of GvHD, emphasizing the relevance of CD4+ T cells and HLA class II associated mHags for development of effective anti-tumor T cell therapies after alloSCT with a low risk for GvHD. The aim of this study was to identify the HLA class II associated mHag that is recognized by CD4+ T cells induced in a patient with relapsed chronic myeloid leukemia (CML) after HLA-matched alloSCT who developed strong GvL reactivity with mild GvHD of the skin after treatment with DLI. We previously developed recombinant bacteria cDNA expression libraries based on delivery of exogenous antigens for identification of HLA class II antigens and used this method for identification of the first autosomal HLA class II (HLA-DQB1*0603) associated mHag LB-PI4K2B-1S. LB-PI4K2B-1S has a population frequency of 40–50% and is encoded by the broadly-expressed phosphatidylinositol 4-kinase type II β gene. In the patient with CML, a polyclonal CD4+ T cell response against LB-PI4K2B-1S and simultaneous mHag specific CD8+ T cells were demonstrated. LB-PI4K2B-1S specific CD4+ T cells were shown to recognize the CD34+ CML cells of the patient as well as other leukemic cells. Recognition and lysis of normal hematopoietic cells by LB-PI4K2B-1S specific CD4+ T cells critically depended on the number of HLA-DQ molecules expressed at the cell surface and was restricted to high HLA-DQ-expressing B cells, mature dendritic cells (DC) and EBV-transformed B cells. HLA-DQ expression on T cells, PHA-stimulated blasts, monocytes and immature DC was absent or low and not sufficient for T cell recognition. We also demonstrated that HLA-DQ expression on normal cells of non-hematopoietic origin after extensive culturing with IFN-γ was moderately upregulated as compared to HLA-DR and -DP and not sufficient for recognition by LB-PI4K2B-1S specific CD4+ T cells. In conclusion, the data suggest that LB-PI4K2B-1S specific CD4+ T cells mediated tumor rejection by directly eliminating the malignant cells of the patient as effector cells and stimulating the induction and maintenance of CD8+ T cell immunity as helper cells, and HLA-DQ associated mHags may be appropriate targets for T cell therapies with the aim to selectively stimulate GvL after HLA-matched alloSCT with a low risk for GvHD.

scholarly journals Human T-Cell Leukemia Virus Type II Directly Acts on CD34+ Hematopoietic Precursors by Increasing Their Survival Potential. Envelope-Associated HLA Class II Molecules Reverse This Effect

Blood ◽  
1998 ◽  
Vol 91 (7) ◽  
pp. 2296-2304
Author(s):  
Claudio Casoli ◽  
Maria Carla Re ◽  
Paola Monari ◽  
Giuliano Furlini ◽  
Giovanna Tosi ◽  
...  
Keyword(s):  
T Cell ◽  
Virus Type ◽  
Leukemia Virus ◽  
Class Ii ◽  
Hla Class Ii ◽  
Type Ii ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Human T Cell ◽  
T Cell Leukemia Virus

The role of human T-cell leukemia virus type II (HTLV-II) in human lymphoproliferative and hematopoietic abnormalities in which the retrovirus can be isolated is still elusive. Here we show that the C344 T-cell–derived lymphotropic HTLV-II type IIa Mo strain acts directly on CD34+ hematopoietic precursors by rescuing them from apoptosis induced by interleukin-3 (IL-3) deprivation. This effect is viral strain-specific, as it is not observed with the B-lymphotropic HTLV-II type IIb Gu strain, it does not require infection of the hematopoietic precursors, and, interestingly, it is strongly dependent on the infected cellular host from which the virus was derived. Indeed, growth adaptation of the Mo strain to the permissive B-cell line, BJAB, renders the virus no longer capable of mediating the antiapoptotic effect. However, pretreatment of the BJAB-adapted Mo strain with antibodies specific for HLA class II, but not class I, histocompatibility antigens restores the antiapoptotic potential of the virus. These results constitute the first evidence that HTLV-II retrovirus can directly influence the homeostasis of human progenitors, without infecting them, and that this crucial activity is strongly inhibited by the presence of host-derived envelope-associated HLA class II antigens.

scholarly journals Targeting Of HLA Class II Restricted Antigens In Graft Versus Leukemia Reactivity

2009 ◽  
Vol 15 (2) ◽  
pp. 114
Author(s):  
J.H.F. Falkenburg ◽  
A. Stumpf ◽  
C.E. Rutten ◽  
E.D. van der Meijden ◽  
S.A.P. Luxemburg-Heijs ◽  
...  
Keyword(s):  
Class Ii ◽  
Hla Class Ii ◽  
Graft Versus Leukemia

scholarly journals Human T-Cell Leukemia Virus Type II Directly Acts on CD34+ Hematopoietic Precursors by Increasing Their Survival Potential. Envelope-Associated HLA Class II Molecules Reverse This Effect

Blood ◽  
1998 ◽  
Vol 91 (7) ◽  
pp. 2296-2304 ◽  
Author(s):  
Claudio Casoli ◽  
Maria Carla Re ◽  
Paola Monari ◽  
Giuliano Furlini ◽  
Giovanna Tosi ◽  
...  
Keyword(s):  
T Cell ◽  
Virus Type ◽  
Leukemia Virus ◽  
Class Ii ◽  
Hla Class Ii ◽  
Type Ii ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Human T Cell ◽  
T Cell Leukemia Virus

Abstract The role of human T-cell leukemia virus type II (HTLV-II) in human lymphoproliferative and hematopoietic abnormalities in which the retrovirus can be isolated is still elusive. Here we show that the C344 T-cell–derived lymphotropic HTLV-II type IIa Mo strain acts directly on CD34+ hematopoietic precursors by rescuing them from apoptosis induced by interleukin-3 (IL-3) deprivation. This effect is viral strain-specific, as it is not observed with the B-lymphotropic HTLV-II type IIb Gu strain, it does not require infection of the hematopoietic precursors, and, interestingly, it is strongly dependent on the infected cellular host from which the virus was derived. Indeed, growth adaptation of the Mo strain to the permissive B-cell line, BJAB, renders the virus no longer capable of mediating the antiapoptotic effect. However, pretreatment of the BJAB-adapted Mo strain with antibodies specific for HLA class II, but not class I, histocompatibility antigens restores the antiapoptotic potential of the virus. These results constitute the first evidence that HTLV-II retrovirus can directly influence the homeostasis of human progenitors, without infecting them, and that this crucial activity is strongly inhibited by the presence of host-derived envelope-associated HLA class II antigens.

scholarly journals HLA Class II Haplotypes Differentiate Between the Adult Autoimmune Polyglandular Syndrome Types II and III

2014 ◽  
Vol 99 (1) ◽  
pp. E177-E182 ◽  
Author(s):  
B. K. Flesch ◽  
N. Matheis ◽  
T. Alt ◽  
C. Weinstock ◽  
J. Bux ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Addison’S Disease ◽  
Class Ii ◽  
Hla Class Ii ◽  
Addison's Disease ◽  
Type Ii ◽  
Autoimmune Thyroid ◽  
Autoimmune Polyglandular Syndrome ◽  
Hla Class Ii Alleles

Background: Genetics of the adult autoimmune polyglandular syndrome (APS) is poorly understood. Aim: The aim of this study was to gain further insight into the genetics of the adult APS types. Site: The study was conducted at a university referral center. Methods: The human leukocyte antigen (HLA) class II alleles, haplotypes, and genotypes were determined in a large cohort of patients with APS, autoimmune thyroid disease (AITD), and type 1 diabetes and in healthy controls by the consistent application of high-resolution typing at a four-digit level. Results: Comparison of the allele and haplotype frequencies significantly discriminated patients with APS vs AITD and controls. The HLA class II alleles DRB1*03:01 *04:01, DQA1*03:01, *05:01, DQB1*02:01, and *03:02 were observed more frequently (P < .001) in APS than in AITD and controls, whereas the alleles DRB1*15:01, DQB1*03:01, and *06:02 were underrepresented in APS vs AITD (Pc < .001) and controls (Pc < .01), respectively. The DRB1*03:01-DQA1*05:01-DQB1*02:01 (DR3-DQ2) and DRB1*04:01-DQA1*03:01:DQB1*03:02 (DRB1*04:01-DQ8) haplotypes were overrepresented in APS (Pc < .001). Combination of both haplotypes to a genotype was highly prevalent in APS vs AITD and controls (Pc < .001). Dividing the APS collective into those with Addison's disease (APS type II) and those without Addison's disease but including type 1 diabetes and AITD (APS type III) demonstrated DR3-DQ2/DRB1*04:01-DQ8 as a susceptibility genotype in APS III (Pc < .001), whereas the DR3-DQ2/DRB1*04:04-DQ8 genotype correlated with APS II (Pc < .001). The haplotypes DRB1*11:01-DQA1*05:05-DQB1*03:01 and DRB1*15:01-DQA1*01:02-DQB1*06:02 are protective in APS III but not in type II (Pc < .01). Conclusions: HLA class II haplotypes differentiate between the adult APS types II and III. Susceptible haplotypes favor the development of polyglandular autoimmunity in patients with AITD.

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