scholarly journals Molecular analysis of T-cell receptor repertoire in bone marrow transplant recipients: evidence for oligoclonal T-cell expansion in graft-versus-host disease lesions

Blood ◽  
1996 ◽  
Vol 87 (7) ◽  
pp. 3032-3044 ◽  
Author(s):  
X Liu ◽  
V Chesnokova ◽  
SJ Forman ◽  
DJ Diamond
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
T Cell Receptor ◽  
Graft Versus Host Disease ◽  
Cell Receptor ◽  
Supporting Evidence ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host ◽  
Beta 2

We have analyzed the T-cell receptor (TCR) V beta repertoire using polymerase chain reaction (PCR) in a cohort of eight patients receiving allogeneic bone marrow transplantation (BMT) from related and unrelated donors at the City of Hope. Results of PCR studies from graft-versus- host disease (GVHD) skin lesions show a bias in the usage of TCR V beta families, whereas examination of peripheral blood (PB) withdrawn at the same time did not reveal a similar phenomenon. In one such family, TCR V beta 2 is predominantly expressed in 7 of 7 biopsy specimens examined. V beta 2 TCR expression from these patients was analyzed more extensively using a combination of individual TCR gene cloning, followed by sequence analysis. We found evidence of oligoclonal expansion of single V beta 2-bearing TCRs in GVHD lesions, and in the PB of some patients after diagnosis of GVHD. In contrast, GVHD-negative biopsy samples showed no evidence for clonotypic TCR amplification. Sequence-specific TCR CDR3 region probes were derived from analysis of the predominant expressed TCR in GVHD lesions, and used to probe Southern blots of amplified V beta 2 TCR mRNA from PB and tissue from BMT recipients and their respective donors. In most cases the probes are highly specific in detecting TCR expression from GVHD lesions alone, although in several instances expression could be detected in PB after GVHD diagnosis. These data provide supporting evidence for the hypothesis that acute GVHD is associated with expansion of T-cell clones expressing antigen-specific TCRs that may contribute to the disease pathology.

scholarly journals HLA-target antigens and T-cell receptor diversity of activated T cells invading the skin during acute graft-versus-host disease

Blood ◽  
1996 ◽  
Vol 87 (6) ◽  
pp. 2345-2353 ◽  
Author(s):  
J Gaschet ◽  
MA Trevino ◽  
M Cherel ◽  
R Vivien ◽  
A Garcia-Sahuquillo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
T Cell Receptor ◽  
Graft Versus Host Disease ◽  
Cell Receptor ◽  
Allogeneic Bone ◽  
T Cell Clones ◽  
Host Disease ◽  
Graft Versus Host ◽  
Cell Clones

To study the repertoire and specificity of T lymphocytes infiltrating skin lesions during graft-versus-host disease (GVHD), we performed an exhaustive molecular and functional analysis of 146 T-cell clones derived from the skin of three patients undergoing an acute GVHD after allogeneic bone marrow transplantation (BMT) from HLA-mismatched related donors. Analysis of T-cell receptor (TCR) rearrangement and TCR chain junctional sequences demonstrated the presence of 11 distinct clones among the 64 derived from patient UPN1, six among the 58 derived from patient UPN2, and seven among the 24 derived from patient UPN3. Three of the 11 T-cell clones from patient UPN1, and all clones from patients UPN2 and UPN3 reacted with mismatched HLA alleles between the bone-marrow donor and recipient. Moreover, both HLA class I (HLA-A2 and -B27) and class II (HLA DP101, DP401, DP1301, DQ8, and DR402) molecules were recognized during this early antihost response. Finally, both TCR alpha and beta chains turned out to be extremely diverse, even within populations of clones derived from the same patient and directed against the same HLA allele. Taken together, these results indicate that any HLA mismatch is potentially targeted during early GVHD, and that the T-cell response at the onset of GVHD is both oligoclonal and highly diversified.

scholarly journals Different T-cell receptor repertoires between lesions and peripheral blood in acute graft-versus-host disease after allogeneic bone marrow transplantation

Blood ◽  
1996 ◽  
Vol 87 (7) ◽  
pp. 3019-3026 ◽  
Author(s):  
K Kubo ◽  
K Yamanaka ◽  
H Kiyoi ◽  
H Fukutani ◽  
M Ito ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
T Cell Receptor ◽  
Allogeneic Bone Marrow Transplantation ◽  
Cell Receptor ◽  
Allogeneic Bone ◽  
Graft Versus Host ◽  
Acute Graft

From the viewpoint of T-cell receptor (TCR) repertoire, we studied the role of T cells in acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (allo-BMT) from an HLA-identical sibling. By means of inverse polymerase chain reaction method and DNA sequencing, we analyzed TCR-alpha and -beta transcripts from GVHD lesions and peripheral blood (PB) in a patient with typical GVHD together with PB from donor. At the initial onset of GVHD, V alpha-7 and -19 subfamilies were oligoclonally expanded in the PB compared with those in the oral mucosal lesions. At the second onset, V alpha-2, and V beta-6 subfamilies were more frequently detected in the cutaneous lesion than in the PB. Some TCR transcripts were recurrently found either in the mucosal or cutaneous lesions (or in both) and not in the PB. Furthermore, some of recurrent TCR transcripts in the lesions shared V gene segments and common motifs of complementarity determining region-3. These findings suggested that T cells infiltrating the GVHD lesions recognized a limited kind of antigens presented by patient's tissues with GVHD, and that T-cell repertoire in the GVHD lesions was different from that in the PB.

Initial treatment of acute graft-versus-host disease with a murine monoclonal antibody directed to the human α/β T cell receptor

1991 ◽  
Vol 34 (2) ◽  
pp. 97-102 ◽  
Author(s):  
Dietrich W. Beelen ◽  
Hans Grosse-Wilde ◽  
Ursula Ryschka ◽  
Klaus Quabeck ◽  
Herbert G. Sayer ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cell ◽  
T Cell Receptor ◽  
Graft Versus Host Disease ◽  
Initial Treatment ◽  
Cell Receptor ◽  
Murine Monoclonal Antibody ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

THE FATE OF DONOR T-CELL RECEPTOR TRANSGENIC T CELLS WITH KNOWN HOST ANTIGEN SPECIFICITY IN A GRAFT-VERSUS-HOST DISEASE MODEL1

1999 ◽  
Vol 68 (1) ◽  
pp. 141-149 ◽  
Author(s):  
Bimalangshu Dey ◽  
Yong-Guang Yang ◽  
Frederic Preffer ◽  
Akira Shimizu ◽  
Kirsten Swenson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Graft Versus Host Disease ◽  
Cell Receptor ◽  
Antigen Specificity ◽  
Host Disease ◽  
Graft Versus Host

SELECTIVE T-CELL-RECEPTOR GENE USAGE IN ALLORECOGNITION AND GRAFT-VERSUS-HOST DISEASE

1993 ◽  
Vol 55 (5) ◽  
pp. 1167-1175 ◽  
Author(s):  
KATSUO YAMANAKA ◽  
WILLIAM W. KWOK ◽  
ERIC M. MICKELSON ◽  
SUSAN MASEWICZ ◽  
FRANK SMITH ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Graft Versus Host Disease ◽  
Receptor Gene ◽  
Cell Receptor ◽  
Host Disease ◽  
Graft Versus Host ◽  
Gene Usage ◽  
T Cell Receptor Gene ◽  
Cell Receptor Gene

Restricted use of T-cell receptor V beta genes in posttransfusion graft- versus-host disease

Transfusion ◽  
1997 ◽  
Vol 37 (11-12) ◽  
pp. 1184-1191 ◽  
Author(s):  
L Wang ◽  
K Tadokoro ◽  
K Tokunaga ◽  
S Uchida ◽  
S Moriyama ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Graft Versus Host Disease ◽  
Cell Receptor ◽  
Host Disease ◽  
Graft Versus Host ◽  
Restricted Use

scholarly journals Gas6 deficiency in recipient mice of allogeneic transplantation alleviates hepatic graft-versus-host disease

Blood ◽  
2010 ◽  
Vol 115 (16) ◽  
pp. 3390-3397 ◽  
Author(s):  
Laurent Burnier ◽  
François Saller ◽  
Linda Kadi ◽  
Anne C. Brisset ◽  
Rocco Sugamele ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Antigen Presenting Cells ◽  
Allogeneic Bone ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Antigen Presenting

Abstract Growth arrest-specific gene 6 (Gas6) is expressed in antigen-presenting cells and endothelial cells (ECs) but not in T cells. When wild-type (WT) or Gas6−/− mice received allogeneic non–T cell–depleted bone marrow cells, hepatic graft-versus-host disease (GVHD) was alleviated in Gas6−/− recipients regardless of donor genotype, but not in WT recipients. T-cell infiltration was more prominent and diffuse in WT than in Gas6−/− recipients' liver. When mice received 0.5 × 106 allogeneic T cells with T cell–depleted allogeneic bone marrow, clinical signs indicated that GVHD was less severe in Gas6−/− than in WT recipients, as shown by a significant improvement of the survival and reduced liver GVHD. These data demonstrate that donor cells were not involved in the protection mechanism. In addition, lack of Gas6 in antigen-presenting cells did not affect WT or Gas6−/− T-cell proliferation. We therefore assessed the response of WT or Gas6−/− ECs to tumor necrosis factor-α. Lymphocyte transmigration was less extensive through Gas6−/− than WT ECs and was not accompanied by increases in adhesion molecule levels. Thus, the lack of Gas6 in ECs impaired donor T-cell transmigration into the liver, providing a rationale for considering Gas6 pathway as a potential nonimmunosuppressive target to minimize GVHD in patients receiving allogeneic hematopoietic stem cell transplantation.

PD-L1 and PD-L2 Protect The Heart In a T-Cell Receptor Transgenic Model Of Graft-Versus Host Disease

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4479-4479
Author(s):  
Kathryn W Juchem ◽  
Britt Anderson ◽  
Cuiling Zhang ◽  
Arlene Sharpe ◽  
Jennifer McNiff ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Weight Loss ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Graft Versus Host Disease ◽  
Cell Receptor ◽  
Graft Versus Host ◽  
Post Transplant ◽  
Donor Bone Marrow

Graft-versus-host disease (GVHD) is a complication of allogeneic stem cell transplantation (alloSCT). In murine models of alloSCT, naive T cells (TN) cause GVHD while effector memory T cells (TEM) do not. To determine why TEM fail to cause GVHD, we generated a novel T-cell receptor transgenic GVHD model. In this model CD4+ TS1 T cells, which recognize an epitope of influenza hemagglutinin (HA), are transferred, along with syngeneic bone marrow, into irradiated transgenic recipients that express HA in all tissues (HA104 Tg mice). We found that TS1 TN induced early and prolonged weight loss and caused GVHD-like pathology in the skin, liver and colon. In contrast, TS1 TEM induced mild, transient weight loss and minimal pathology, demonstrating that TEM have repertoire-independent characteristics that limit their ability to induce GVHD. Post transplant analysis revealed that TS1 TEM progeny, relative to TS1 TN progeny, produced less IFN-γ, proliferated and accumulated less in the colon, and expressed higher levels of the inhibitory molecule PD-1. To investigate whether PD-1 was responsible for limiting pathogenesis by TEM, we used hosts and donor bone marrow lacking both PD-L1 and PD-L2. The absence of PD-L1/2 did not enable TS1 TEM to cause early weight loss. However, between 35 and 60 days post transplant, TS1 TEM recipients lacking PD-L1/2 rapidly began losing weight and approximately 50% died. Weight loss in TEM recipients was dependent upon lack of PD-L1/2 expression on both donor bone marrow and host cells, including radioresistant stromal cells, suggesting a possible role for PD-L1/2 expressed in tissues. Indeed, global absence of PD-L1 alone, which (in contrast to PD-L2) is expressed on parenchymal tissues, also resulted in late weight loss in recipients given TEM. To determine the reason for late weight loss, we surveyed tissue histopathology. Surprisingly, in the absence of PD-L1/2, TEM recipients did not develop exacerbated colon pathology but instead developed mononuclear infiltrates and mycocyte necrosis in the heart, accompanied by heart block and decreased cardiac output. Interestingly, heart disease was also seen in PD-L1/2 deficient TN recipients that survived to later time points, indicating that the protective role of PD-L1/2 applied more generally to GVHD induced by CD4 T cells. Strikingly, the extensive infiltrates in affected hearts were mostly comprised of non-TS1 T cells, including both CD4 and CD8 cells. These cells are likely host-derived, as severe cardiac infiltrates were seen when Rag-deficient donor BM was used to reconstitute host hematopoiesis. We therefore hypothesize that in GVHD PD-L1/2 normally prevent “allogeneic” T cell mediated damage but also protect from subsequent syngeneic T cell-mediated pathogenesis that could contribute to prolonged disease. This effect is tissue specific and could in part be due to parenchymal expression of PD-L1 in certain organs. It is possible that such mechanisms could explain more chronic phases of GVHD, which differs from acute GVHD. Ongoing depletion experiments will determine the relative contributions of donor TS1 T cells, donor bone marrow derived T cells and host T cells. Disclosures: No relevant conflicts of interest to declare.

BB02 Improves Therapeutical Effectiveness Of Extracorporeal Photopheresis With 8-MOP In a Murine Model Of Graft-Versus-Host Disease

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5416-5416
Author(s):  
David Garcia-Bernal ◽  
Miguel Blanquer ◽  
Jose Antonio del Rio ◽  
Enrique Correal ◽  
Maria del Carmen Algueró ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Murine Model ◽  
Lethal Dose ◽  
Therapeutic Effectiveness ◽  
Allogeneic Bone ◽  
Extracorporeal Photopheresis ◽  
Host Disease ◽  
Graft Versus Host

Abstract Introduction Extracorporeal photopheresis (ECP) is a cell-based immunomodulatory therapy involving the separation of peripheral blood autologous mononuclear cells followed by ex-vivo administration of 8-methoxypsoralen (8-MOP) and UVA radiation before reinfusion. ECP is efficient for the treatment of multiple diseases mediated by unregulated T cell populations, such as cutaneous T cell lymphoma, autoinmune diseases or graft-versus-host disease (GVHD), the major complication after allogeneic bone marrow transplantation. Our aim in the present work was to compare the therapeutic effectiveness of 8-MOP with other two new compounds (BB01 and BB02) in a experimental murine model of GVHD. Methods Murine GVHD was induced after transplanting bone marrow cells and splenocytes from donor Balb/c mice into C57Bl6J recipients previously conditioned with a lethal dose of 10 Gy split into two doses of 5 Gy spaced 24 hours apart. To investigate the therapeutic effectiveness of ECP with either 8-MOP, BB01 or BB02, splenocytes from separate cohorts of C57Bl6J with GVHD were isolated 12 days after transplantation, incubated with the different compounds, irradiated with UVA light and injected intravenously once a week for four weeks. Survival after transplantation was monitored daily and clinical GVHD was graded using a previously described score analyzing weight loss, posture (hunching), activity, skin integrity and fur texture (Cooke et al, 1996). Mice of each group were evaluated and graded from 0 to 2 for each criterion, obtaining a clinical index by summation of the five criteria scores (maximum index=10). Results Mice treated weekly with BB02 showed a significant higher survival than those treated with 8-MOP (p=0,038), while BB01 had a similar effect to that of 8-MOP. Mice treated with either compound improved their clinical GVHD score compared to untreated mice group, being significantly lower with BB02 than with BB01 and 8-MOP (p=0,023). Conclusions BB02 was more efficient than 8-MOP in the reversal of murine GVHD, while BB01 showed the same therapeutic effectiveness than 8-MOP. Acknowledgments Work financed by the Spanish Ministry of Science and Innovation (Ref: BFU2010-19599) and the Spanish Net of Cell Therapy (TerCel) from Institute of Health Carlos III. Disclosures: No relevant conflicts of interest to declare.

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