Effect of IL-22 on intestinal stem cells, GVHD-related tissue damage, and GVL.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6539-6539
Author(s):  
Alan M. Hanash ◽  
Marcel R. M. Van Den Brink ◽  
Guoqiang Hua ◽  
Richard Kolesnick ◽  
Bruce R. Blazar
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
T Cell ◽  
Allogeneic Bone Marrow Transplantation ◽  
Lymphoid Cells ◽  
Receptor Expression ◽  
Intestinal Stem Cells ◽  
Allogeneic Bone ◽  
Epithelial Regeneration ◽  
Donor T Cells

6539 Background: Intestinal graft vs. host disease (GVHD) is a major complication of allogeneic bone marrow transplantation (allo-BMT). Strategies to limit GVHD by selective promotion of epithelial regeneration in the absence of immunosuppression are largely unknown. Methods: We investigated the role of IL-22 in allo-BMT by utilizing wild type and IL-22 knockout (KO) mice as donors or recipients in allo-BMT. Results: We found that administration of an anti-IL-22 neutralizing antibody to allo-BMT recipients during the first month post-BMT led to increased GVHD mortality, indicating that IL-22 functioned to reduce GVHD severity post-BMT. In contrast, use of IL-22 KO donor T cells did not impair their ability to eliminate A20 lymphoma cells upon tumor challenge, thus indicating that IL-22 was not essential for donor T cells to mediate graft vs. lymphoma (GVL) responses. BMT with WT donors and recipients indicated that IL-22 levels in small and large intestine were increased after BMT and after radiation injury (RI) without BMT. IL-22 upregulation after RI was dependent on the presence of IL-23p40. Although intestinal IL-22 levels were increased after T cell-depleted (TCD) BMT, intestinal IL-22 was reduced by GVHD, as IL-22 production was mediated by host-derived innate lymphoid cells (ILC) that were eliminated by GVHD. Furthermore, host-derived IL-22 was critical for reduction of GVHD morbidity, mortality, and intestinal pathology. GVHD in IL-22 KO mice led to increased apoptosis in epithelial crypts where the intestinal epithelial stem/progenitor cell niche is located. Immunohistochemistry and immunofluorescence demonstrated IL-22 receptor expression on intestinal stem cells (ISC) and progenitors. Allo-BMT in Lgr5-LacZ reporter mice indicated that ISC were targeted by GVHD, and GVHD in IL-22 KO mice led to dramatic ISC depletion. Conclusions: IL-22 is critical for protection of host epithelium during GVHD and critical for protection of ISC, and it does not contribute to donor T cell GVL responses. These findings may have broad relevance for protection of ISC and intestinal epithelium in clinical GVHD and other inflammatory intestinal diseases, and may be useful for clinical separation of pathologic GVH and therapeutic GVL responses.

scholarly journals Donor T-cell alloreactivity against host thymic epithelium limits T-cell development after bone marrow transplantation

Blood ◽  
2007 ◽  
Vol 109 (9) ◽  
pp. 4080-4088 ◽  
Author(s):  
Mathias M. Hauri-Hohl ◽  
Marcel P. Keller ◽  
Jason Gill ◽  
Katrin Hafen ◽  
Esther Pachlatko ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Marrow Transplantation ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone Marrow ◽  
Thymic Epithelial Cells ◽  
Allogeneic Bone ◽  
Donor T Cells

Abstract Acute graft-versus-host disease (aGVHD) impairs thymus-dependent T-cell regeneration in recipients of allogeneic bone marrow transplants through yet to be defined mechanisms. Here, we demonstrate in mice that MHC-mismatched donor T cells home into the thymus of unconditioned recipients. There, activated donor T cells secrete IFN-γ, which in turn stimulates the programmed cell death of thymic epithelial cells (TECs). Because TECs themselves are competent and sufficient to prime naive allospecific T cells and to elicit their effector function, the elimination of host-type professional antigen-presenting cells (APCs) does not prevent donor T-cell activation and TEC apoptosis, thus precluding normal thymopoiesis in transplant recipients. Hence, strategies that protect TECs may be necessary to improve immune reconstitution following allogeneic bone marrow transplantation.

scholarly journals NK cells mediate reduction of GVHD by inhibiting activated, alloreactive T cells while retaining GVT effects

Blood ◽  
2010 ◽  
Vol 115 (21) ◽  
pp. 4293-4301 ◽  
Author(s):  
Janelle A. Olson ◽  
Dennis B. Leveson-Gower ◽  
Saar Gill ◽  
Jeanette Baker ◽  
Andreas Beilhack ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Fas Ligand ◽  
Nk Cell ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Alloreactive T Cells ◽  
Donor T Cells ◽  
The Impact

Abstract Natural killer (NK) cells suppress graft-versus-host disease (GVHD) without causing GVHD themselves. Our previous studies demonstrated that allogeneic T cells and NK cells traffic similarly after allogeneic bone marrow transplantation (BMT). We therefore investigated the impact of donor NK cells on donor alloreactive T cells in GVHD induction. Animals receiving donor NK and T cells showed improved survival and decreased GVHD score compared with controls receiving donor T cells alone. Donor T cells exhibited less proliferation, lower CD25 expression, and decreased interferon-γ (IFN-γ) production in the presence of NK cells. In vivo, we observed perforin- and Fas ligand (FasL)–mediated reduction of donor T cell proliferation and increased T cell apoptosis in the presence of NK cells. Further, activated NK cells mediated direct lysis of reisolated GVHD-inducing T cells in vitro. The graft-versus-tumor (GVT) effect was retained in the presence of donor NK cells. We demonstrate a novel mechanism of NK cell–mediated GVHD reduction whereby donor NK cells inhibit and lyse autologous donor T cells activated during the initiation of GVHD.

scholarly journals Analysis of T-cell repopulation after allogeneic bone marrow transplantation: significant differences between recipients of T-cell depleted and unmanipulated grafts

Blood ◽  
1996 ◽  
Vol 87 (9) ◽  
pp. 3984-3992 ◽  
Author(s):  
E Roux ◽  
C Helg ◽  
F Dumont-Girard ◽  
B Chapuis ◽  
M Jeannet ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Allogeneic Bone Marrow Transplantation ◽  
Cell Receptor ◽  
Allogeneic Bone ◽  
Receptor Repertoire ◽  
Donor T Cells ◽  
Circulating T Cells ◽  
Cell Repopulation

We have studied the repopulation of the T-cell compartment in 27 patients transplanted with bone marrow from an (HLA)-identical sibling. Significant differences were found between recipients of unmanipulated and T-cell depleted grafts. Analysis of the T cells by a method based on amplification of minisatellite DNA regions showed that without depletion > 99.9% of the clones responding to a mitogenic stimulus after transplantation were of donor origin. In contrast, when the graft had been depleted with Campath-1M plus complement, a significant part of the T cells cloned during the first weeks after transplantation comprised of recipient T cells that had survived the preconditioning. This mixed population of low numbers donor and recipient T cells (19 +/- 31/mm3 at day 14) expanded rapidly (predominantly CD8+ T cells) during the first 2 months, without a significant change of the ratio of recipient/donor T cells. In 11 of 17 evaluable patients a late wave ( > 9 months) of donor T cells occurred. As a consequence, T-cell chimerism changed in favor of donor T cells and the CD4/CD8 ratio that had been reversed ( < 0.5) after the first expansion, normalized (1.5 +/- 0.51). Analysis of the T-cell receptor repertoire showed that in recipients of a T-cell depleted graft, the recipient as well as the donor T cells that repopulated the peripheral T-cell pool during the first month, were the progeny of a limited number of precursors. Because without depletion, when larger numbers of donor T cells had been cotransfused with the marrow, the repertoire was much more diverse, these data show that immediately after transplantation, the peripheral pool is repopulated primarily through expansion of circulating T cells.

scholarly journals Absence of donor T-cell–derived soluble TNF decreases graft-versus-host disease without impairing graft-versus-tumor activity

Blood ◽  
2007 ◽  
Vol 110 (2) ◽  
pp. 783-786 ◽  
Author(s):  
Chiara Borsotti ◽  
Anna R. K. Franklin ◽  
Sydney X. Lu ◽  
Theo D. Kim ◽  
Odette M. Smith ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host ◽  
Tnf Α ◽  
Donor T Cells ◽  
Membrane Bound

Abstract Tumor necrosis factor (TNF) plays an important role in graft-versus-host disease (GVHD) and graft-versus-tumor (GVT) activity after allogeneic bone marrow transplantation (allo-BMT). TNF can be expressed in a membrane-bound form (memTNF) and as a soluble (solTNF) molecule after being cleaved by the TNF-α converting enzyme (TACE). To study the contribution of donor T-cell–derived memTNF versus solTNF in GVHD and GVT, we used mice containing a noncleavable allele in place of endogenous TNF (memTNFΔ/Δ) as donors in murine BMT models. Recipients of memTNF T cells developed significantly less GVHD than recipients of wild-type (wt) T cells. In contrast, GVT activity mediated by memTNF T cells remained intact, and alloreactive memTNF T cells showed no defects in proliferation, activation, and cytotoxicity. These data suggest that suppressing the secretion of solTNF by donor T cells significantly decreases GVHD without impairing GVT activity.

Donor T Cells Lacking IFN-Gamma Receptor Expression Enhance Donor Myeloid Engraftment and Decrease Early Acute Graft-Versus-Host Disease Mortality Following Allogeneic Bone Marrow Transplantation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3514-3514
Author(s):  
Kai Sun ◽  
Minghui Li ◽  
Mark A. Hubbard ◽  
Lisbeth A. Welniak ◽  
William J. Murphy
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone Marrow ◽  
Allogeneic Bone ◽  
Ifn Gamma ◽  
Graft Versus Host ◽  
Gamma Receptor ◽  
Donor T Cells

Abstract Lack of engraftment, graft-versus-host disease (GVHD) and tumor relapse are major issues that affect clinical outcome after allogeneic bone marrow transplantation (allo-BMT). Donor T cells in the graft present a dilemma in allo-BMT due to both the beneficial and deleterious clinical effects they can exert. Therefore, modulation of donor T cell function may represent a potential therapeutic approach in allo-BMT. In murine allo-BMT models, It has been demonstrated that donor T cell-derived IFN-gamma is required for optimal graft-versus-tumor (GVT) responses but it also plays complex roles by exhibiting both protective and pathogenic effects in GVHD development. We therefore investigated the role of IFN-gamma responsiveness by the donor T cells in allo-BMT through the use of IFN-gamma receptor deficient (IfnR−/−; RKO) mice. In these experiments, recipient BALB/c (H2d) mice received lethal total body irradiation. Irradiation was followed by the infusion of graded doses of T cell-depleted (TCD) allogeneic bone marrow cells (5 or 15 × 106) intravenously from major histocompatibility complex (MHC)-disparate wild type (WT) C57BL/6 (H2b, IfnR+/+) mice, with or without 0.5 × 106 T cells (or 3 × 106 splenocytes as a source of allogeneic T cells) from either WT (H2b, IfnR+/+) or RKO mice. Compared with transplantation of WT TCD-BMCs with T cells from a WT donor, we found that transplantation of WT TCD-BMCs with RKO T cells resulted in marked and significant increases in myeloid engraftment as determined by CFU-GM, peripheral neutrophil and platelet counts during the early phase of allo-BMT. Consistently, a significant increase serum G-CSF was also found on day 7 after allo-BMT with this group. This enhanced myeloid engraftment by RKO T cells occurred only in murine allo-BMT but not syngeneic BMT models, indicating it is a property of alloreactivity. Interestingly, no significant differences in donor T cell engraftment, nor in the percentage of Treg, Th17, CD4+ or CD8+ T cell subsets and IFN-gamma+ T cells, were observed in spleen. However, on day 7 after allo-BMT, significantly fewer donor T cells were observed in the gut in the recipient of RKO T cells compared to recipients of WT T cells. This reduction of donor T cells in gut was associated with a significant decrease in early acute GVHD lethality. This novel finding suggests transplantation of T cells lacking IFN-gamma receptors resulted in less donor T cell homing to the gut during the early phase of allo-BMT. We next addressed the ability of donor RKO T cells to provide GVT responses. A20 tumor-bearing BALB/c (H2d) mice were transplanted with WT C57BL/6 TCD-BMC. Compared with transplantation of 1 × 106 WT T cells with WT TCD-BMC, co-transplantation of 1 × 106 RKO T cells with WT TCD-BMC resulted in less GVHD-related mortality with greater anti-tumor effects. Taken together, these observations suggest that targeting IFN-gamma receptor signaling on donor T cells may help to improve the efficacy of allo-BMT by promoting donor myeloid engraftment and decreasing early acute GVHD lethality with greater GVT potential due to altered lymphocyte homing.

Lack of Host Bone Marrow-Derived Interleukin-12 Increased the Incidence of Allograft Rejection in Allogeneic Bone Marrow Transplantation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2960-2960
Author(s):  
Ying Wang ◽  
Jian-Ming Li ◽  
Wayne A.C. Harris ◽  
Cynthia R. Giver ◽  
Edmund K Waller
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Allogeneic Bone Marrow Transplantation ◽  
Interleukin 12 ◽  
Allogeneic Bone ◽  
Radiation Chimeras ◽  
Allogeneic Bmt ◽  
Donor T Cells

Abstract Abstract 2960 Background: Donor cell engraftment following allogeneic bone marrow transplantation (BMT) is affected by several factors, including immunological major histocompatibility complex (MHC) barriers, the intensity of the conditioning regimen, and the content of T-cells in the graft. The current model for engraftment in allogeneic BMT is that host dendritic cells (DCs) activate donor T-cells which promote engraftment by eliminating radio-resistant cytotoxic host immune cells, especially natural killer (NK) cells and T-cells. To explore the interaction between donor T-cell and host antigen-presenting cells (APC) in engraftment in allogeneic BMT, we focused on the role of interleukin-12 (IL-12), a key cytokine produced mainly by DCs that drives the development of donor type 1 helper T cells (Th1) and type 1 cytotoxic T lymphocytes (Tc1). Methods: Radiation chimeras with >95% donor chimerism were created by transplanting 5 × 106 bone marrow (BM) cells from IL-12 knock out (IL-12 KO) or wild type (WT) B6 (H-2Kb, CD45.2) donors into congenic BL6 Pepboy (B6.SJL-PtprcaPep3b/BoyJ, H-2Kb, CD45.1) mice following lethal 11 Gy irradiation. A second allogeneic BMT was conducted 2 months later using MHC mismatched FVB (H-2q, CD45.1), BA.B10 (H-2Kk, CD45.2, CD90.1) or B10.BR (H-2Kk, CD45.2, CD90.2) donor cells. In vivo bioluminescent imaging (BLI) was performed to analyze the number and in vivo distribution of luciferase+ donor T-cells. The whole-body bioluminescent signal was used as a marker of the donor T cell expansion. Engraftment of donor myeloid cells was determined by flow cytometry using mAbs for specific leukocyte markers expressed on donors and recipients (CD45.1, CD45.2, H-2Kb). Intracellular cytokine expression (IL-4, IL-10, IFN-g) by donor CD4+ and CD8+ T cells was analyzed by flow cytometry. Results: WT BL6→BL6 radiation chimeras recipients showed greater expansion of luciferase+ donor T-cells compared with IL-12 KO BL6→BL6 radiation chimeras recipients and FVB→FVB syngeneic recipients at early time point (2 wks) following 9 Gy re-irradiation and transplantation of 3 × 105 luciferase+ FVB-L2G85 T-cells in combination with 5 × 106 T cell depleted (TCD) BM cells from FVB mice following (Fig 1). At 4 weeks post transplant, more WT BL6→BL6 radiation chimeras achieved myeloid engraftment than IL-12 KO BL6→BL6 radiation chimera recipients(75.0% versus 33.3% respectively, p = 0.086), and the former group had better erythroid engraftment than the latter group (RBC 8.65 ± 1.88 × 1012/L versus 5.67 ± 2.22 × 1012/L respectively, p = 0.011). However, when FVB, WT BL6→BL6 or IL-12 KO BL6→BL6 radiation chimeras recipients were conditioned with a larger dose of irradiation prior to the second transplantation (10 Gy) and received a larger dose of donor T-cells (5 × 105), both the WT BL6→BL6 and IL-12 KO BL6→BL6 radiation chimeras recipients achieved full donor engraftments (85.7% versus 87.5% respectively, p = NS). Donor T cells in allogeneic BMT recipients were Th1/Tc1 polarized, there were no differences in frequencies and total numbers of Th1/Tc1 donor CD4+ and CD8+ T cells comparing recipients of WT BL6→BL6 and IL-12 KO BL6→BL6 radiation chimeras. In spite of an increased irradiation dose and larger number of donor T-cells in the second transplant regimen, no increase in graft versus host disease (GVHD) clinical scores and GVHD-mortality were observed in the recipients of WT BL6→BL6 radiation chimeras compared with recipients of IL-12 KO BL6→BL6 radiation chimeras. Conclusion: These data support a role for host BM-derived IL-12 in facilitating engraftment in allogeneic BMT following a reduced dose (9 Gy) radiation. The lack of host BM-derived IL-12 expression led to allograft rejection. Rejection could be overcome by increasing the dose of pre-transplant irradiation and the content of donor T-cells without causing lethal GVHD. As the main source of host BM-derived IL-12, recipient APC thus play an important role in donor T-cell activation. As has been previously demonstrated in a murine BMT model, the addition of IL-12 in the peri-transplant period helped to separate graft versus leukemia effects from the GVHD-promoting activity of donor T-cells (Yang, 1997). Patients predicted to be high risk of graft failure may benefit from treatment strategies that contribute to production of IL-12 during the early phases of hematopoietic engraftment. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Targeting Interleukin-2-Inducible T-Cell Kinase (ITK) Differentiates GVL and GVHD in Allo-HSCT

2020 ◽  
Vol 11 ◽  
Author(s):  
Mahinbanu Mammadli ◽  
Weishan Huang ◽  
Rebecca Harris ◽  
Aisha Sultana ◽  
Ying Cheng ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Interleukin 2 ◽  
Treatment Strategies ◽  
Receptor Expression ◽  
Hematopoietic Stem ◽  
Target Organs ◽  
Donor T Cells ◽  
Inducible T Cell Kinase

Allogeneic hematopoietic stem cell transplantation is a potentially curative procedure for many malignant diseases. Donor T cells prevent disease recurrence via graft-versus-leukemia (GVL) effect. Donor T cells also contribute to graft-versus-host disease (GVHD), a debilitating and potentially fatal complication. Novel treatment strategies are needed which allow preservation of GVL effects without causing GVHD. Using murine models, we show that targeting IL-2-inducible T cell kinase (ITK) in donor T cells reduces GVHD while preserving GVL effects. Both CD8+ and CD4+ donor T cells from Itk-/- mice produce less inflammatory cytokines and show decrease migration to GVHD target organs such as the liver and small intestine, while maintaining GVL efficacy against primary B-cell acute lymphoblastic leukemia (B-ALL). Itk-/- T cells exhibit reduced expression of IRF4 and decreased JAK/STAT signaling activity but upregulating expression of Eomesodermin (Eomes) and preserve cytotoxicity, necessary for GVL effect. Transcriptome analysis indicates that ITK signaling controls chemokine receptor expression during alloactivation, which in turn affects the ability of donor T cells to migrate to GVHD target organs. Our data suggest that inhibiting ITK could be a therapeutic strategy to reduce GVHD while preserving the beneficial GVL effects following allo-HSCT treatment.

scholarly journals Keratinocyte growth factor enhances DNA plasmid tumor vaccine responses after murine allogeneic bone marrow transplantation

Blood ◽  
2009 ◽  
Vol 113 (7) ◽  
pp. 1574-1580 ◽  
Author(s):  
Robert R. Jenq ◽  
Christopher G. King ◽  
Christine Volk ◽  
David Suh ◽  
Odette M. Smith ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Keratinocyte Growth Factor ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Effector Cells ◽  
Cd8 Cells ◽  
T Cell Reconstitution ◽  
Dna Plasmid

Abstract Keratinocyte growth factor (KGF), which is given exogenously to allogeneic bone marrow transplantation (allo-BMT) recipients, supports thymic epithelial cells and increases thymic output of naive T cells. Here, we demonstrate that this improved T-cell reconstitution leads to enhanced responses to DNA plasmid tumor vaccination. Tumor-bearing mice treated with KGF and DNA vaccination have improved long-term survival and decreased tumor burden after allo-BMT. When assayed before vaccination, KGF-treated allo-BMT recipients have increased numbers of peripheral T cells, including CD8+ T cells with vaccine-recognition potential. In response to vaccination, KGF-treated allo-BMT recipients, compared with control subjects, generate increased numbers of tumor-specific CD8+ cells, as well as increased numbers of CD8+ cells producing interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). We also found unanticipated benefits to antitumor immunity with the administration of KGF. KGF-treated allo-BMT recipients have an improved ratio of T effector cells to regulatory T cells, a larger fraction of effector cells that display a central memory phenotype, and effector cells that are derived from a broader T-cell–receptor repertoire. In conclusion, our data suggest that KGF can function as a potent vaccine adjuvant after allo-BMT through its effects on posttransplantation T-cell reconstitution.

scholarly journals Imbalances within the peripheral blood T-helper (CD4+) and T-suppressor (CD8+) cell populations in the reconstitution phase after human bone marrow transplantation

Blood ◽  
1988 ◽  
Vol 71 (5) ◽  
pp. 1196-1200 ◽  
Author(s):  
A Velardi ◽  
A Terenzi ◽  
S Cucciaioni ◽  
R Millo ◽  
CE Grossi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Peripheral Blood ◽  
Marrow Transplantation ◽  
Allogeneic Bone Marrow Transplantation ◽  
T Cell Subsets ◽  
Allogeneic Bone ◽  
T Helper

Abstract Peripheral blood T cell subsets were evaluated in 11 patients during the reconstitution phase after allogeneic bone marrow transplantation and compared with 11 age-matched controls. The proportion of cells coexpressing Leu7 and CD11b (C3bi receptor) markers was determined within the CD4+ (T-helper) and the CD8+ (T-suppressor) subsets by two- color immunofluorescence analysis. CD4+ and CD8+ T cells reached normal or near-normal values within the first year posttransplant. In contrast to normal controls, however, most of the cells in both subsets coexpressed the Leu7 and CD11b markers. T cells with such phenotype display the morphological features of granular lymphocytes (GLs) and a functional inability to produce interleukin 2 (IL 2). These T cell imbalances were not related to graft v host disease (GvHD) or to clinically detectable virus infections and may account for some defects of cellular and humoral immunity that occur after bone marrow transplantation./

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.

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