scholarly journals Regulation of a Graft-Versus-Leukemia Effect by Major Histocompatibility Complex Class II Molecules on Leukemia Cells: HLA-DR1 Expression Renders K562 Cell Tumors Resistant to Adoptively Transferred Lymphocytes in Severe Combined Immunodeficiency Mice/Nonobese Diabetic Mice

Blood ◽  
1997 ◽  
Vol 90 (11) ◽  
pp. 4553-4558 ◽  
Author(s):  
Frank F. Weichold ◽  
Yin-zheng Jiang ◽  
Daniel E. Dunn ◽  
Michael Bloom ◽  
Vera Malkovska ◽  
...  
Keyword(s):  
Mhc Class Ii ◽  
Nk Cell ◽  
Severe Combined Immunodeficiency ◽  
Nod Mice ◽  
Class Ii ◽  
Leukemia Cells ◽  
Combined Immunodeficiency ◽  
Histocompatibility Complex ◽  
Proliferation In Vitro

Abstract To understand the role of key molecules in determining the strength and nature of allogeneic T-cell response to leukemia, we transfected HLA-DR1 into the major histocompatibility complex (MHC)-deficient, natural killer (NK)-cell sensitive K562 leukemia cell line. Untransfected K562 cells stimulated NK proliferation in vitro and formed subcutaneous tumors in severe combined immunodeficiency/non-obese diabetic (SCID/NOD) mice. Tumor growth was inhibited by adoptive intravenous transfer of fresh unprimed peripheral blood mononuclear cells (PBMC). In contrast, HLA-DR1 transfected cells stimulated CD4+ T cells, but not NK-cell proliferation in vitro and formed tumors resistant to fresh PBMC in SCID/NOD mice. Tumors not expressing MHC were infiltrated with CD16+CD56+ lymphocytes whereas nonregressing HLA-DR1 expressing tumors showed only a scanty infiltration with both T-cell and NK-cell subsets. The results indicate that MHC class II expression by leukemia cells can determine the effector cell type that it engages. In vivo MHC class II expression rendered K562 cell tumors resistant to NK-cell mediated antitumor reactivity.

scholarly journals Regulation of a Graft-Versus-Leukemia Effect by Major Histocompatibility Complex Class II Molecules on Leukemia Cells: HLA-DR1 Expression Renders K562 Cell Tumors Resistant to Adoptively Transferred Lymphocytes in Severe Combined Immunodeficiency Mice/Nonobese Diabetic Mice

Blood ◽  
1997 ◽  
Vol 90 (11) ◽  
pp. 4553-4558
Author(s):  
Frank F. Weichold ◽  
Yin-zheng Jiang ◽  
Daniel E. Dunn ◽  
Michael Bloom ◽  
Vera Malkovska ◽  
...  
Keyword(s):  
Mhc Class Ii ◽  
Nk Cell ◽  
Severe Combined Immunodeficiency ◽  
Nod Mice ◽  
Class Ii ◽  
Leukemia Cells ◽  
Combined Immunodeficiency ◽  
Histocompatibility Complex ◽  
Proliferation In Vitro

To understand the role of key molecules in determining the strength and nature of allogeneic T-cell response to leukemia, we transfected HLA-DR1 into the major histocompatibility complex (MHC)-deficient, natural killer (NK)-cell sensitive K562 leukemia cell line. Untransfected K562 cells stimulated NK proliferation in vitro and formed subcutaneous tumors in severe combined immunodeficiency/non-obese diabetic (SCID/NOD) mice. Tumor growth was inhibited by adoptive intravenous transfer of fresh unprimed peripheral blood mononuclear cells (PBMC). In contrast, HLA-DR1 transfected cells stimulated CD4+ T cells, but not NK-cell proliferation in vitro and formed tumors resistant to fresh PBMC in SCID/NOD mice. Tumors not expressing MHC were infiltrated with CD16+CD56+ lymphocytes whereas nonregressing HLA-DR1 expressing tumors showed only a scanty infiltration with both T-cell and NK-cell subsets. The results indicate that MHC class II expression by leukemia cells can determine the effector cell type that it engages. In vivo MHC class II expression rendered K562 cell tumors resistant to NK-cell mediated antitumor reactivity.

scholarly journals HLA-DM Interactions with Intermediates in HLA-DR Maturation and a Role for HLA-DM in Stabilizing Empty HLA-DR Molecules

1996 ◽  
Vol 184 (6) ◽  
pp. 2153-2166 ◽  
Author(s):  
Lisa K. Denzin ◽  
Craig Hammond ◽  
Peter Cresswell
Keyword(s):  
Mhc Class Ii ◽  
Antigen Processing ◽  
Class Ii ◽  
Physical Interaction ◽  
Antigenic Peptides ◽  
Histocompatibility Complex ◽  
Chain Complexes ◽  
Hla Dr

Major histocompatibility complex (MHC) class II–positive cell lines which lack HLA-DM expression accumulate class II molecules associated with residual invariant (I) chain fragments (class II–associated invariant chain peptides [CLIP]). In vitro, HLA-DM catalyzes CLIP dissociation from class II–CLIP complexes, promoting binding of antigenic peptides. Here the physical interaction of HLA-DM with HLA-DR molecules was investigated. HLA-DM complexes with class II molecules were detectable transiently in cells, peaking at the time when the class II molecules entered the MHC class II compartment. HLA-DR αβ dimers newly released from I chain, and those associated with I chain fragments, were found to associate with HLA-DM in vivo. Mature, peptide-loaded DR molecules also associated at a low level. These same species, but not DR-I chain complexes, were also shown to bind to purified HLA-DM molecules in vitro. HLA-DM interaction was quantitatively superior with DR molecules isolated in association with CLIP. DM-DR complexes generated by incubating HLA-DM with purified DR αβCLIP contained virtually no associated CLIP, suggesting that this superior interaction reflects a prolonged HLA-DM association with empty class II dimers after CLIP dissociation. Incubation of peptide-free αβ dimers in the presence of HLA-DM was found to prolong their ability to bind subsequently added antigenic peptides. Stabilization of empty class II molecules may be an important property of HLA-DM in facilitating antigen processing.

scholarly journals Analysis of the Role of  Variation of Major Histocompatibility Complex Class II Expression on Nonobese Diabetic (NOD) Peripheral T Cell Response

1998 ◽  
Vol 188 (12) ◽  
pp. 2267-2275 ◽  
Author(s):  
William M. Ridgway ◽  
Hiroaki Ito ◽  
Marcella Fassò ◽  
Chen Yu ◽  
C. Garrison Fathman
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Transgenic Mice ◽  
Mhc Class Ii ◽  
Nod Mice ◽  
Class Ii ◽  
Nonobese Diabetic ◽  
Histocompatibility Complex

The current paradigm of major histocompatibility complex (MHC) and disease association suggests that efficient binding of autoantigens by disease-associated MHC molecules leads to a T cell–mediated immune response and resultant autoimmune sequelae. The data presented below offer a different model for this association of MHC with autoimmune diabetes. We used several mouse lines expressing different levels of I-Ag7 and I-Ak on the nonobese diabetic (NOD) background to evaluate the role of MHC class II in the previously described NOD T cell autoproliferation. The ratio of I-Ag7 to I-Ak expression correlated with the peripheral T cell autoproliferative phenotype in the mice studied. T cells from the NOD, [NOD × NOD.I-Anull]F1, and NOD I-Ak transgenic mice demonstrated autoproliferative responses (after priming with self-peptides), whereas the NOD.H2h4 (containing I-Ak) congenic and [NOD × NOD.H2h4 congenic]F1 mice did not. Analysis of CD4+ NOD I-Ak transgenic primed lymph node cells showed that autoreactive CD4+ T cells in the NOD I-Ak transgenic mice were restricted exclusively by I-Ag7. Considered in the context of the avidity theory of T cell activation and selection, the reported poor peptide binding capacity of NOD I-Ag7 suggested a new hypothesis to explain the effects of MHC class II expression on the peripheral autoimmune repertoire in NOD mice. This new explanation suggests that the association of MHC with diabetes results from “altered” thymic selection in which high affinity self-reactive (potentially autoreactive) T cells escape negative selection. This model offers an explanation for the requirement of homozygous MHC class II expression in NOD mice (and in humans) in susceptibility to insulin-dependent diabetes mellitus.

scholarly journals Determinant capture as a possible mechanism of protection afforded by major histocompatibility complex class II molecules in autoimmune disease.

1993 ◽  
Vol 178 (5) ◽  
pp. 1675-1680 ◽  
Author(s):  
H Deng ◽  
R Apple ◽  
M Clare-Salzler ◽  
S Trembleau ◽  
D Mathis ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Antigen Processing ◽  
Nod Mice ◽  
Insulin Dependent Diabetes Mellitus ◽  
Class Ii ◽  
Dependent Diabetes Mellitus ◽  
Protective Effects ◽  
Major Histocompatibility ◽  
Histocompatibility Complex

How peptide-major histocompatibility complex (MHC) class II complexes are naturally generated is still unknown, but accumulating evidence suggests that unfolding proteins or long peptides can become bound to class II molecules at the dominant determinant before proteolytic cleavage. We have compared the immunogenicity of hen egg-white lysozyme (HEL) in nonobese diabetic (NOD), (NOD x BALB/c)F1, and E(d) alpha transgenic NOD mice. We find that a response to the subdominant ANOD-restricted determinant disappears upon introduction of an E(d) molecule, and is restored when scission of HEL separates this determinant from its adjoining, competitively dominant, E(d)-restricted determinant. This suggests that the E(d) molecule binds and protects its dominant determinant on a long peptide while captured neighboring determinants are lost during proteolysis. These results provide clear evidence for "determinant capture" as a mechanism of determinant selection during antigen processing and a possible explanation for MHC-protective effects in insulin-dependent diabetes mellitus.

scholarly journals Antigen-unspecific B Cells and Lymphoid Dendritic Cells Both Show Extensive Surface Expression of Processed Antigen–Major Histocompatibility Complex Class II Complexes after Soluble Protein Exposure In Vivo or In Vitro

1997 ◽  
Vol 186 (5) ◽  
pp. 673-682 ◽  
Author(s):  
Guangming Zhong ◽  
Caetano Reis e Sousa ◽  
Ronald N. Germain
Keyword(s):  
Dendritic Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
B Cells ◽  
Mhc Class Ii ◽  
T Cell Activation ◽  
Cell Activation ◽  
Class Ii ◽  
Histocompatibility Complex

Intravenous (i.v.) injection of high amounts of soluble proteins often results in the induction of antigen-specific tolerance or deviation to helper rather than inflammatory T cell immunity. It has been proposed that this outcome may be due to antigen presentation to T cells by a large cohort of poorly costimulatory or IL-12–deficient resting B cells lacking specific immunoglobulin receptors for the protein. However, previous studies using T cell activation in vitro to assess antigen display have failed to support this idea, showing evidence of specific peptide–major histocompatibility complex (MHC) class II ligand only on purified dendritic cells (DC) or antigen-specific B cells isolated from protein injected mice. Here we reexamine this question using a recently derived monoclonal antibody specific for the T cell receptor (TCR) ligand formed by the association of the 46-61 determinant of hen egg lysozyme (HEL) and the mouse MHC class II molecule I-Ak. In striking contrast to conclusions drawn from indirect T cell activation studies, this direct method of TCR ligand analysis shows that i.v. administration of HEL protein results in nearly all B cells in lymphoid tissues having substantial levels of HEL 46-61–Ak complexes on their surface. DC readily isolated from spleen also display this TCR ligand on their surface. Although the absolute number of displayed ligands is greater on such DC, the relative specific ligand expression compared to total MHC class II levels is similar or greater on B cells. These results demonstrate that in the absence of activating stimuli, both lymphoid DC and antigen-unspecific B cells present to a similar extent class II–associated peptides derived from soluble proteins in extracellular fluid. The numerical advantage of the TCR ligand–bearing B cells may permit them to interact first or more often with naive antigen-specific T cells, contributing to the induction of high-dose T cell tolerance or immune deviation.

scholarly journals Bone marrow transplantation in major histocompatibility complex class II deficiency: a single-center study of 19 patients

Blood ◽  
1995 ◽  
Vol 85 (2) ◽  
pp. 580-587
Author(s):  
C Klein ◽  
M Cavazzana-Calvo ◽  
F Le Deist ◽  
N Jabado ◽  
M Benkerrou ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Major Histocompatibility Complex ◽  
Bone Marrow Transplantation ◽  
Mhc Class Ii ◽  
Marrow Transplantation ◽  
Class Ii ◽  
Combined Immunodeficiency ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Mhc Class Ii Deficiency

Major histocompatibility complex (MHC) class II deficiency (bare lymphocyte syndrome) is a rare inborn error of the immune system characterized by impaired antigen presentation and combined immunodeficiency. It causes severe and unremitting infections leading to progressive liver and lung dysfunctions and death during childhood. As in other combined immunodeficiency disorders, bone marrow transplantation (BMT) is considered the treatment of choice for MHC class II deficiency. We analyzed the files of 19 patients who have undergone BMT in our center. Of the 7 patients who underwent HLA- identical BMT, 3 died in the immediate posttransplant period of severe viral infections, whereas the remaining 4 were cured, with recovery of normal immune functions. Of the 12 patients who underwent HLA-haplo- identical BMT, 3 were cured, 1 was improved by partial engraftment, 7 died of infectious complications due to graft failure or rejection, and 1 is still immunodeficient because of engraftment failure. A favorable outcome in the HLA-non-identical BMT group was associated with an age of less than 2 years at the time of transplantation. All the patients with stable long-term engraftment had persistently low CD4 counts after transplantation (105 to 650/microL at last follow up), but no clear susceptibility to opportunistic infections despite persisting MHC class II deficiency on thymic epithelium and other nonhematopoietic cells. We conclude that HLA-identical and -haploidentical BMT can cure MHC class II deficiency, although the success rate of haploidentical BMT is lower than that in other combined immunodeficiency syndromes. HLA- haploidentical BMT should preferably be performed in the first 2 years of life, before the acquisition of chronic virus carriage and sequelae of infections.

scholarly journals Genetic evidence for a new type of major histocompatibility complex class II combined immunodeficiency characterized by a dyscoordinate regulation of HLA-D alpha and beta chains.

1996 ◽  
Vol 183 (3) ◽  
pp. 1063-1069 ◽  
Author(s):  
J Douhan ◽  
I Hauber ◽  
M M Eibl ◽  
L H Glimcher
Keyword(s):  
Major Histocompatibility Complex ◽  
Cell Lines ◽  
Mhc Class Ii ◽  
Genetic Disorder ◽  
Class Ii ◽  
Genetic Evidence ◽  
Combined Immunodeficiency ◽  
Major Histocompatibility ◽  
Histocompatibility Complex

Major histocompatibility complex (MHC) class II combined immunodeficiency (CID), also known as type II bare lymphocyte syndrome, is an autosomal recessive genetic disorder characterized by the complete lack of expression of MHC class II antigens. The defect results from a coordinated lack of transcription of all class II genes. Cell fusion studies using many patient- and experimentally derived class II-negative cell lines have identified four distinct genetic complementation groups. In this report, we present genetic evidence that cell lines derived from two newly described MHC class II-deficient patients, KER and KEN, represent a fifth complementation group. In addition, the KER and KEN cell lines display a unique pattern of dyscoordinate regulation of their MHC class II genes, which is reflected in a new phenotype of in vivo promoter occupancy as revealed by in vivo genomic footprinting. These data point to a new defect that can result in the MHC class II-deficient phenotype.

scholarly journals A Mechanism for the Major Histocompatibility Complex–linked Resistance to Autoimmunity

1997 ◽  
Vol 186 (7) ◽  
pp. 1059-1075 ◽  
Author(s):  
Dennis Schmidt ◽  
Joan Verdaguer ◽  
Nuzhat Averill ◽  
Pere Santamaria
Keyword(s):  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Pancreatic Beta Cell ◽  
Nod Mice ◽  
Class Ii ◽  
Major Histocompatibility ◽  
Nonobese Diabetic ◽  
Histocompatibility Complex ◽  
Nonobese Diabetic Mice ◽  
Mhc Class Ii Genes

Certain major histocompatibility complex (MHC) class II haplotypes encode elements providing either susceptibility or dominant resistance to the development of spontaneous autoimmune diseases via mechanisms that remain undefined. Here we show that a pancreatic beta cell–reactive, I-Ag7–restricted, transgenic TCR that is highly diabetogenic in nonobese diabetic mice (H-2g7) undergoes thymocyte negative selection in diabetes-resistant H-2g7/b, H-2g7/k, H-2g7/q, and H-2g7/nb1 NOD mice by engaging antidiabetogenic MHC class II molecules on thymic bone marrow–derived cells, independently of endogenous superantigens. Thymocyte deletion is complete in the presence of I-Ab, I-Ak + I-Ek or I-Anb1 + I-Enb1 molecules, partial in the presence of I-Aq or I-Ak molecules alone, and absent in the presence of I-As molecules. Mice that delete the transgenic TCR develop variable degrees of insulitis that correlate with the extent of thymocyte deletion, but are invariably resistant to diabetes development. These results provide an explanation as to how protective MHC class II genes carried on one haplotype can override the genetic susceptibility to an autoimmune disease provided by allelic MHC class II genes carried on a second haplotype.

scholarly journals Bone marrow transplantation in major histocompatibility complex class II deficiency: a single-center study of 19 patients

Blood ◽  
1995 ◽  
Vol 85 (2) ◽  
pp. 580-587 ◽  
Author(s):  
C Klein ◽  
M Cavazzana-Calvo ◽  
F Le Deist ◽  
N Jabado ◽  
M Benkerrou ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Major Histocompatibility Complex ◽  
Bone Marrow Transplantation ◽  
Mhc Class Ii ◽  
Marrow Transplantation ◽  
Class Ii ◽  
Combined Immunodeficiency ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Mhc Class Ii Deficiency

Abstract Major histocompatibility complex (MHC) class II deficiency (bare lymphocyte syndrome) is a rare inborn error of the immune system characterized by impaired antigen presentation and combined immunodeficiency. It causes severe and unremitting infections leading to progressive liver and lung dysfunctions and death during childhood. As in other combined immunodeficiency disorders, bone marrow transplantation (BMT) is considered the treatment of choice for MHC class II deficiency. We analyzed the files of 19 patients who have undergone BMT in our center. Of the 7 patients who underwent HLA- identical BMT, 3 died in the immediate posttransplant period of severe viral infections, whereas the remaining 4 were cured, with recovery of normal immune functions. Of the 12 patients who underwent HLA-haplo- identical BMT, 3 were cured, 1 was improved by partial engraftment, 7 died of infectious complications due to graft failure or rejection, and 1 is still immunodeficient because of engraftment failure. A favorable outcome in the HLA-non-identical BMT group was associated with an age of less than 2 years at the time of transplantation. All the patients with stable long-term engraftment had persistently low CD4 counts after transplantation (105 to 650/microL at last follow up), but no clear susceptibility to opportunistic infections despite persisting MHC class II deficiency on thymic epithelium and other nonhematopoietic cells. We conclude that HLA-identical and -haploidentical BMT can cure MHC class II deficiency, although the success rate of haploidentical BMT is lower than that in other combined immunodeficiency syndromes. HLA- haploidentical BMT should preferably be performed in the first 2 years of life, before the acquisition of chronic virus carriage and sequelae of infections.

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