Graft-versus-host disease develops in mice transplanted with lymphocyte-depleted bone marrow cells from signal-transducing adaptor protein-2 transgenic mice

2021 ◽  
Vol 537 ◽  
pp. 118-124
Author(s):  
Hideaki Saito ◽  
Michiko Ichii ◽  
Jun Toda ◽  
Yuichi Kitai ◽  
Ryuta Muromoto ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Transgenic Mice ◽  
Graft Versus Host Disease ◽  
Bone Marrow Cells ◽  
Adaptor Protein ◽  
Host Disease ◽  
Graft Versus Host ◽  
Marrow Cells

Third Party Cytokine-Induced Killer Cells Protect from Murine Lethal Graft-Versus-Host Disease

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3092-3092
Author(s):  
Rie Kuroda ◽  
Shintaro Mase ◽  
Toshihiro Fujiki ◽  
Hideaki Maeba ◽  
Raita Araki ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Graft Versus Host Disease ◽  
Murine Model ◽  
Bone Marrow Cells ◽  
Third Party ◽  
Host Disease ◽  
Graft Versus Host ◽  
Cik Cells ◽  
Marrow Cells

Abstract Cell adoptive immunotherapy protect from lethal graft-versus-host disease (GVHD) while preserving graft-versus-tumor effects is ideal in allogeneic hematopoietic stem cell transplantation (HSCT) in patients with hematologic malignancies. Moreover, the use of third party cells would open a huge source of availability and feasibility across major histocompatibility barriers. In fact, some studies demonstrated that infusion of third party derived cells such as whole bone marrow cells or iNKT cells could ameliorate lethal GVHD in a murine model. Cytokine-induced killer (CIK) cells are ex vivo-expanded T lymphocytes expressing both natural killer and T-cell markers. We have previously reported that donor-type CIK cells have potential to separate graft-versus-tumor effects from GVHD by eliminating host dendritic cells due to the enhanced killing activity by interferon-gamma. Actually, donor-typed CIKs infusion for refractory hematological malignancies after HSCT has been started in some clinical trails. In the present study, we examine the effect of third party cells against GVHD protection, in particular third party CIK cells for prevention from lethal GVHD in a murine model of allogeneic HSCT. To test this, lethally irradiated host Balb/c (H-2d) mice were given C3H (H-2k) or B6 (H-2b) bone marrow cells and splenocytes to induce lethal GVHD with/without third-party cells (C57/BL6 or C3H) such as CIK cells, whole splenocytes, or bone marrow derived dendritic cells (BMDCs) on day 0, which were cultured from bone marrow cells with GM-CSF. Mice receiving third party CIK cells showed much less GVHD and significant survival benefit compared those with third party splenocytes, or BMDCs as shown in the figure below. Interestingly, when infusion of third party splenocytes was delayed until day 4 after bone marrow transplantation, host mice receiving splenocytes survived much better compared with mice receiving splenocytes on day 0, even though reduced number of third party splenocytes was used. This result indicated that timing of third party cell infusion was quite important, especially when third party splenocytes were used. As expected, the mice given reduced number of third CIK cells also showed excellent survival with much less GVHD. Taken together, our results clearly demonstrated that third party CIK cells have strong potential to prevent lethal GVHD without attention to timing of cell infusion. Next, to further investigate the advantage of third party CIK cells rather than whole splenocytes, we compared the hematological reconstitution between the mice given third party CIK cells on day 4 after BMT and whole splenocytes. Both mice showed much less GVHD with the same level, however the recovery of white blood cell count on day 21 after BMT was significantly better in the mice receiving third party CIK cells. In conclusion, infusion of third party CIK cells has strong potential to prevent lethal GVHD with faster hematological recovery after HSCT. Disclosures No relevant conflicts of interest to declare.

THY1+ BONE MARROW CELLS REGULATE THE INDUCTION OF MURINE SYNGENEIC GRAFT-VERSUS-HOST DISEASE

1993 ◽  
Vol 56 (4) ◽  
pp. 941-944 ◽  
Author(s):  
J. SCOTT BRYSON ◽  
C. DARRELL JENNINGS ◽  
BETTY E. CAYWOOD ◽  
ALAN M. KAPLAN
Keyword(s):  
Bone Marrow ◽  
Graft Versus Host Disease ◽  
Bone Marrow Cells ◽  
Host Disease ◽  
Graft Versus Host ◽  
Marrow Cells

Comparison of Pathology Transform of Liver, Spleen, Intestinal Tract and Skin with Acute Graft-Versus-Host Disease in Mice.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5238-5238
Author(s):  
Chunyan Wang ◽  
Huo Tan ◽  
Zhenqian Huang ◽  
Huanzhu Zhang ◽  
Kunyuan Guo
Keyword(s):  
Bone Marrow ◽  
Survival Time ◽  
Graft Versus Host Disease ◽  
Intestinal Tract ◽  
Bone Marrow Cells ◽  
Host Disease ◽  
Graft Versus Host ◽  
Irradiation Group ◽  
Acute Graft ◽  
Marrow Cells

Abstract Objective: To study the pathology transform of liver, spleen, intestinal tract and skin with acute graft-versus-host disease after myeloablative MHC mismatched BMT in mice. Methods: The murine model of MHC mismatched BMT was established by using (BALB/c H-2d mouse as the recipient, and C57BL/6H-2b mouse as the donor. 30 recipient mouse were divided into 3 groups (n=10) after irradiation (TBI 60Co 9.0Gy). simple-irradiation group, MHC mismatched GVHD group: the BALB/c H-2d mice were conditioned with 9.0Gy, after a interval of four hours followed by infusion of C57BL/6H-2b mice bone marrow cells (1×107/one) and spleen cells (3×107/one). syngeneic BMT group: C57BL/6H-2b mice were conditioned with 9.0Gy, after a interval of four hours followed by infusion of C57BL/6H-2b mice bone marrow cells (1×107/one). The effect was assessed by hemotopoietic reconstruction, survival time, body weight, histopathology in the recipients. Rasults: Life span: survival time was (5.23±0.78) days for the simple-irradiation group, survival time was (14.67±2.34)days for MHC mismatched GVHD group, beyond 30 days for syngeneic BMT group. Pathology results: GVHD pathology manifestation were found in MHC mismatched GVHD group. The severity of GVHD pathology transform in mice were based on the occurrence time of GVHD. The GVHD pathology transform of liver, spleen, intestinal tract and skin in the same mouse were not parallel which GVHD pathology transform of spleen was the severest, the nest were intestinal tract and skin, GVHD pathology transform of liver was the trivial, even more normal. 3 of 10 in GVHD group had skin III-IV GVHD, but normal liver. Conclusion: The result have shown that the onset time of liver GVHD in four organs was the last in myeloablative MHC mismatched BMT in mice.

Donor-derived IL-15 is critical for acute allogeneic graft-versus-host disease

Blood ◽  
2005 ◽  
Vol 105 (2) ◽  
pp. 894-901 ◽  
Author(s):  
Bradley W. Blaser ◽  
Sameek Roychowdhury ◽  
Daniel J. Kim ◽  
Noah R. Schwind ◽  
Darshna Bhatt ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Cell Function ◽  
Bone Marrow Cells ◽  
Effector Memory ◽  
F1 Hybrid ◽  
Host Disease ◽  
Graft Versus Host ◽  
Marrow Cells

AbstractInterleukin-15 (IL-15) is a pleiotropic proinflammatory cytokine with inefficient posttranscriptional processing. We hypothesized that endogenous IL-15 could affect disease progression in the well-described C57Bl/6 (B6) → (C57Bl/6 × DBA/2) F1 hybrid (B6D2F1) murine model of acute allogeneic graft-versus-host disease (GVHD). B6D2F1 allogeneic recipients received transplants of IL-15-/- B6 bone marrow cells or B6 bone marrow cells expressing a murine IL-15 transgene (IL-15 tg) modified for efficient translation and secretion. Mice that received transplants of IL-15-/- B6 bone marrow cells displayed a significantly longer median survival time (MST) compared with mice that received transplants of wild-type (wt) B6 bone marrow; in contrast, mice that received transplants of IL-15 tg B6 bone marrow cells had a dramatically decreased MST. This decrease in survival was associated with a substantial activation and expansion of effector-memory (CD44highCD62Llow) CD8+ T lymphocytes. Finally, in vivo depletion of either CD4+ or CD8+ T lymphocyte subsets significantly prolonged survival in mice receiving IL-15 tg B6 marrow, while depletion of both CD4+ and CD8+ T cells provided complete protection from acute GVHD. We thus show that acute GVHD is attenuated in the absence of donor bone marrow–derived IL-15 and conclude that donor-derived IL-15 is a critical mediator of T-cell function in acute GVHD.

FTY720-Induced Sequestration of Donor T Cells in Lymph Nodes Leads to Activation-Induced Apoptosis of Alloreactive T Cells and Reduced Graft-Versus-Host Disease.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3061-3061
Author(s):  
Daigo Hashimoto ◽  
Shoji Asakura ◽  
Ken-ichi Matsuoka ◽  
Yukimi Sakoda ◽  
Mitsune Tanimoto ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Lymph Nodes ◽  
Graft Versus Host Disease ◽  
Bone Marrow Cells ◽  
Graft Versus Host ◽  
Allogeneic Bmt ◽  
Donor T Cells ◽  
Ifn Γ ◽  
Marrow Cells

Abstract Interaction of donor T cells and host antigen-presenting cells (APCs) in secondary lymphoid organs is critical for inducing graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT). Activation-induced cell death (AICD) is a chief mechanism of clonal deletion that is responsible for the rapid contraction of alloreactive donor T cells following an initial massive expansion. We hypothesized that sequestration of donor T cells in lymph nodes (LNs) would lead to prolonged interaction of donor T cells and host APCs in LNs and cause AICD of alloreactive donor T cells after allogeneic BMT. To test this hypothesis, recipient mice were given FTY720, which inhibits migration of T cells from LNs, after BMT. Lethally irradiated B6 (H-2b) mice were injected with 10 x 106 purified T cells and 5 x 106 bone marrow cells harvested from congeneic B6.Ly-5a (H-2b, CD45.1+) donors. FTY720 was administered by daily oral gavage at a dose of 0.3mg/kg from day 0. Six days after congeneic BMT, numbers of donor T cells in mesenteric LNs were greater in FTY720-treated mice as expected. By contrast, when B6D2F1 (H-2b/d) recipients were transplanted with 4 x 106 purified T cells and 5 x 106 bone marrow cells from allogeneic B6. Ly-5a donors, numbers of donor T cells in mesenteric LNs were greater in FTY720-treated mice than controls 4 days after allogeneic BMT but were subsequently less in FTY720-treated mice than controls (Figure). Five days after allogeneic BMT, frequencies of apoptotic donor T cells assessed by AnnexinV positivity were significantly greater in FTY720-treated mice (33±3 vs 24±5%, P<.05) than those in controls. Serum level of IFN-γ (7.4±1.1 ng/ml vs 12.4±1.6 ng/ml, P<.05), an index of systemic T cell responses, was significantly reduced in FTY720-treated mice on day7. These results suggest that administration of FTY720 enhances contraction of donor T cells by inducing apoptosis of donor T cells after allogeneic BMT. This FTY720-induced reduction of serum levels of IFN-γ was similarly observed when Fas-deficient B6-lpr/lpr mice were used as donors, indicating Fas-independent AICD in this phenomenon. Administration of FTY720 until day10 after allogeneic BMT improved survivals of recipients (67% vs 0% at day 21, P<.05). When reduced number of T cells (1 x 106) were infused, administration of FTY720 until day10 improved clinical GVHD scores (6.0±0.5 vs 4.1±0.3 at day14, P<.05) and survivals (100% vs 50% at day 30, P<.05) of recipients. Next, 1 x 106 donor T cells isolated from FTY720-treated and control-treated recipients 6 days after allogeneic BMT were adoptively transferred to lethally irradiated B6D2F1 mice together with 2 x 106 bone marrow cells from syngeneic B6D2F1 donors. T cells from FTY720-treated mice caused significantly decreased GVH reaction compared to T cells from control-treated mice (p<.01), suggesting the reduced alloreactivity of T cells from FTY720-treated mice. These findings suggest that FTY720 could modulate GVHD by the induction of AICD of donor T cells in LNs as well as by the inhibition of migration of donor T cells to target tissue. Figure Figure

Immunodominant Minor Histocompatibility Antigen-Specific T Lymphocytes Eradicate BCR-ABL-Induced B-ALL and CML without Causing Graft-Versus-Host Disease in Mice.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3686-3686
Author(s):  
Yiguo Hu ◽  
Thomas Sproule ◽  
Cong Peng ◽  
Linghong Kong ◽  
Ami Goodrich ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Lymphocytes ◽  
Graft Versus Host Disease ◽  
Leukemic Cells ◽  
Leukemia Cell Line ◽  
Leukemia Cells ◽  
Host Disease ◽  
Graft Versus Host ◽  
Activated T Lymphocytes ◽  
Marrow Cells

Abstract Adoptive immunotherapy of human Philadelphia chromosome-positive (Ph+) leukemia has not been effective due to difficulties of identifying tumor-specific antigens for the disease. It has been reported that T lymphocytes activated by some minor histocompatibility antigens (mHAs) can efficiently treat mice receiving HL4 cells (a leukemia cell line) without causing graft-versus-host disease (GVHD). We investigated whether this anti-mHA immunotherapeutic strategy is applicable to treating Ph+ leukemia that includes B-ALL (B-cell acute lymphoblastic leukemia) and CML (chronic myeloid leukemia). Because the mHA, H60, is an immunodominant mHA among H7, H28, and H58 in mice (Choi et al, Immunity 17:593–603, 2002), we tested whether H60 can serve as an immunotherapeutic target in the treatment of B-ALL and CML in our retroviral bone marrow transduction/transplantation disease models (Li et al, J Exp Med189:1399–1412, 1999). We used C57BL/6-H60 congenic mouse splenocytes to immunize wild type C57BL/6 (B6) mice that do not have the H60 gene, and the activated T lymphocytes from the immunized B6 mice were injected into mice with BCR-ABL-induced B-ALL or CML (3×107 cells/mouse). We found that H60-specific T lymphocytes at a single dose completely eliminated leukemic cells within 10 days after the injection of the cells and cured B-ALL and CML, however, in mice receiving donor bone marrow cells transduced with empty vector and treated with H60-specific T lymphocytes, the non-BCR-ABL-expressing donor marrow cells lasted for more than 4 weeks, suggesting that H60-activated T lymphocytes have much stronger inhibitory effect on BCR-ABL-expressing leukemic cells than on normal marrow cells. In contrast, leukemia mice receiving naïve T lymphocytes died within 3 to 4 weeks post BCR-ABL induction of leukemia. Six months later, no residual leukemia cells were detected in the spleen and bone morrow of the leukemia mice receiving H60-activated T lymphocytes. In addition, no GVHD was observed in the mice. We also use H7/H28/H60 triple congenic B6 mice in our study, and found that H7/H28/H60-primed T lymphocytes were more effective in elimination of leukemia cells in mice compared with when the single H60 antigen was used in similar experiment. Especially, the H7/H28/H60-primed T lymphocytes were highly effective in treating B-ALL mice, and did not induce GVHD. These results indicate that mHAs are promising targets for immunotherapy of BCR-ABL-induced B-ALL and CML.

Novel Anti-Fibrotic Therapies for Experimental Chronic Graft-Versus-Host Disease.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4490-4490 ◽  
Author(s):  
Bernd M. Spriewald ◽  
Pawel Zerr ◽  
Alfiya Akhmetshina ◽  
Andreas Mackensen ◽  
Georg Schett ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Weight Loss ◽  
Graft Versus Host Disease ◽  
Research Funding ◽  
Bone Marrow Cells ◽  
Chronic Gvhd ◽  
Host Disease ◽  
Graft Versus Host ◽  
Dermal Thickness ◽  
Activated Fibroblasts

Abstract Abstract 4490 Background Chronic graft-versus host disease (cGvHD) can result in a scleroderma-like disease with dermal, pulmonary and gastrointestinal fibrosis. The histopathological hallmark of sclerodermatous chronic GvHD is accumulation of extracellular matrix proteins by pathologically activated fibroblasts, caused at least in part by the profibrotic cytokines TGF-β and PDGF. It was shown recently that the family of abl kinases plays an important role in the activation of matrix synthesis. Here we investigated whether imatinib and nilotinib, both targeting specifically TGF-β and PDGF signaling pathways by inhibiting the tyrosine kinase activity of c-abl and PDGF receptors, could reduce cGvHD in a murine model. Material and Methods Recipient mice (BALB/c, H2d) received total body irradiation (2×6 Gy), followed by 1×10∧6 bone marrow cells and 2×10∧6 splenocytes from B10.D2 donors (H2d, multiple minor mismatches). Recipients receiving syngeneic bone marrow and spleen cells served as control. The treatment of transplanted mice started 12 to 14 days post transplantation. Imatinib (150 mg/kg) was given per os once daily and nilotinib (37.5 mg/kg) was administrated per os twice daily until 6 weeks after bone marrow transplantation. Observed skin changes were documented using a clinical score. After 6 weeks dermal thickness was determined by staining with hematoxylin and eosin and activated fibroblasts by using immunohistochemistry for alpha smooth muscle actin. Collagen concentration in afflicted skin was analyzed with the hydroxyproline assay. Results Untreated mice receiving an allogeneic transplant, in contrast to syngeneic controls, showed clinical features of cutaneous cGvHD, including skin lesions with alopecia and a lower mobility, in addition to diarrhea and weight loss until 6 weeks after alloBMT. Treatment of recipients with imatinib and nilotinib resulted in serum concentrations comparable to those achieved in humans by standard dosing. Application of imatinib or nilotinib completely prevented the development of cutaneous cGvHD including alopecia and skin ulceration, and was effective in preventing weight loss. Compared to untreated recipients dermal thickness was decreased by 100 ± 8 % (p = 0.001) with imatinib and by 54 ± 14 % (p = 0.016) with nilotinib. The numbers of myofibroblasts were reduced by 84 ± 16 % (p = 0.001) with imatinib and by 87 ± 18 % (p = 0.002) with nilotinib. Furthermore, the collagen content in afflicted skin was reduced by 83 ± 15 % with imatinib and by 94 ± 14 % with nilotinib. Conclusions The combined inhibition of c-abl and PDGFR by imatinib or nilotinib was effective for the prevention of sclerodermatous chronic GvHD. The data support recent clinical observations of the potential effect of imatinib in fibrotic chronic graft-versus-host disease. Disclosures: Spriewald: Novartis: Research Funding. Off Label Use: Imatinib and Nilotinib as anti-fibrotic drug in the prevention and treatment of chronic graft-versus-host disease.. Distler:Novartis: Research Funding.

scholarly journals Lethal graft-versus-host disease after bone marrow transplantation across minor histocompatibility barriers in mice. Prevention by removing mature T cells from marrow.

1978 ◽  
Vol 148 (6) ◽  
pp. 1687-1698 ◽  
Author(s):  
R Korngold ◽  
J Sprent
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Marrow Transplantation ◽  
Host Disease ◽  
Graft Versus Host ◽  
High Incidence ◽  
Marrow Cells

In two situations, transfer of normal unsensitized bone marrow cells into heavily irradiated H-2-identical allogeneic mice caused a high incidence of lethal chronic graft-versus-host disease (GVHD), i.e. mortality occuring between days of 20 and 80 postirradiation. Minor histocompatibility determinants appeared to be the main target for eliciting GVHD. Removing mature T cells from the marrow with anti-Thy 1.2 serum and complement before injection prevented GVHD. On the basis of adding purified T cells to T-cell-depleted marrow cells, it was concluded that contamination of the marrow with as few as 0.3% T cells was sufficient to cause a high incidence of lethal GVHD in certain situations. No GVHD was found with the injection of non-T cells (Thy 1.2-negative cells) or with tolerant T cells. Irradiated recipients of T-cell-depleted marrow cells remained in good health for prolonged periods. These mice showed extensive chimerism with respect to the donor marrow, normal numbers of T and B cells and were immunocompetent. The data provide no support for the view that chronic GVHD developing after bone marrow transplantation in man is the result of an attack by the progeny of the donor stem cells. The results imply that mature T cells contaminating marrow inocula are probably the main cause of GVHD seen in the clinical situation.

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