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.

Allogeneic Cytokine-Induced Killer Cells Kill Dendritic Cells Efficiently Resulting in Less Graft-Versus-Host Disease

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4308-4308
Author(s):  
Shintaro Mase ◽  
Hideaki Maeba ◽  
Rie Kuroda ◽  
Raita Araki ◽  
Toshihiro Fujiki ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Bone Marrow Transplantation ◽  
Nk Cells ◽  
Graft Versus Host Disease ◽  
Marrow Transplantation ◽  
Host Disease ◽  
Graft Versus Host ◽  
Killing Activity ◽  
Cik Cells

Abstract Abstract 4308 Cytokine-induced killer (CIK) cells are ex vivo–expanded T lymphocytes expressing both natural killer (NK)– and T-cell markers. We have reported that adoptive transfer of allogeneic CIK cells in a murine model caused minimal graft-versus-host disease (GVHD) with retention of antitumor activity mediated by NKG2D, which is an activating receptor expressed on NK cells. The mechanism of suppression of GVHD after allogeneic bone marrow transplantation is, in part, due to the abundant production of IFN-gamma from the CIK cells, which has protective effect against GVHD. We have also demonstrated that allogeneic CIK cells displayed a significant lower acquisition of homing molecules, required for the entry of inflamed and GVHD target organs (a4b7, CCR9, E-selectin, CXCR3, and CCR5) and a higher susceptibility to apoptosis compared to allogeneic splenocytes. There also might be some causes other than we mentioned above. Host residual dendritic cells (DCs) have a crucial role for initiating GVHD reaction, because they present recipient alloantigens to donor T cells, which finally attack on recipient tissues. Murine alloreactive NK cells, even when infused in large numbers, do not cause GVHD in the mouse by killing recipient DCs. Similarly, it remains a possibility that the reduced GVHD in CIK cells receiving mice was due to the elimination of residual host DCs by CIK cells. To test this, DCs generated from bone marrow cells with the addition of GM-CSF were used for 51Cr release cytotoxicity assays as target cells. Although autologous CIK cells (Balb/c) had relatively strong killing activity against DCs (Balb/c), allogeneic CIK cells (B6) had much more killing activity even from at a 5:1 effector-target ratio as shown below. Allogeneic CD8+ cells did not show any killing activity against DCs. In addition, killing activity against DCs did not changed with/without adding NKG2D blocking antibody, suggesting that other mechanisms to undergo cell lysis should exist in CIK cells in addition to NKG2D/NKG2D ligand system, which are mainly involved in tumor eradication. To further evaluate whether allogeneic CIK cells kill host DCs in vivo, lethally irradiated Balb/c recipients were given BM (B6) with CIK cells or splenocytes to compare the percent of residual host-typed DCs in the spleen five days after bone marrow transplantation. Percent of host-typed DCs tended to be lower in the mice receiving alllogeneic CIK cells compared with those receiving fresh splenocytes or BM alone. In conclusion, allogeneic CIK cells caused less GVHD due in part to elimination of host DCs. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Hematopoietic reconstitution and prevention of graft-versus-host disease with UVB-irradiated haploidentical murine spleen and marrow cells

Blood ◽  
1991 ◽  
Vol 78 (12) ◽  
pp. 3317-3322
Author(s):  
ML Cohn ◽  
RA Cahill ◽  
HJ Deeg
Keyword(s):  
Graft Versus Host Disease ◽  
Murine Model ◽  
Bone Marrow Cells ◽  
Chronic Gvhd ◽  
Skin Grafts ◽  
Spleen Cells ◽  
Host Disease ◽  
Uvb Irradiation ◽  
Graft Versus Host ◽  
Marrow Cells

We investigated in a murine model whether UVB irradiation of lymphohemopoietic cells would prevent the development of graft-versus- host disease (GVHD). Preliminary experiments showed that spleen colony (CFU-S) formation by hemopoietic cells was preserved at UVB doses that eliminated lymphocyte proliferation. In a parent into F1 model, UVB irradiation (5 to 15 mJ/cm2) of spleen cells added to normal marrow cells prevented the development of GVHD, whereas all recipients given untreated spleen cells developed GVHD. Syngeneic recipients of marrow exposed to 2.5 to 10 mJ/cm2 of UVB achieved normal hemopoietic reconstitution. Based on these observations, B6D2 F1 (H-2b x H-2d) recipients were given 1,000 cGy of total body irradiation (TBI) followed by transplantation of 5 x 10(6) parental B6 (H-2b) bone marrow cells and 10 x 10(6) B6 spleen cells, either unirradiated or exposed to UVB before infusion. All mice transplanted with cells exposed to 10 or 12.5 mJ/cm2 of UVB survived without GVHD. At 2.5 and 5.0 mJ/cm2, mice showed signs of GVHD, beginning at day 30, and 100% and 80%, respectively, eventually developed chronic GVHD. At 7.5 mJ/cm2, mice had weight loss, from which 60% recovered and survived without GVHD, while 40% died with GVHD. At 15 mJ/cm2, some recipients died from graft failure, while some survived without GVHD. All surviving mice were complete donor-type chimeras. Spleen size and cellularity and in vitro lymphocyte responses correlated inversely with the development of GVHD. Mice without GVHD showed specific tolerance to skin grafts from the second parent strain, while animals with GVHD rejected their skin grafts. Thus, in a murine model UVB irradiation of transplanted hemopoietic stem cells allows for hemopoietic reconstitution and prevents GVHD.

scholarly journals Hematopoietic reconstitution and prevention of graft-versus-host disease with UVB-irradiated haploidentical murine spleen and marrow cells

Blood ◽  
1991 ◽  
Vol 78 (12) ◽  
pp. 3317-3322 ◽  
Author(s):  
ML Cohn ◽  
RA Cahill ◽  
HJ Deeg
Keyword(s):  
Graft Versus Host Disease ◽  
Murine Model ◽  
Bone Marrow Cells ◽  
Chronic Gvhd ◽  
Skin Grafts ◽  
Spleen Cells ◽  
Host Disease ◽  
Uvb Irradiation ◽  
Graft Versus Host ◽  
Marrow Cells

Abstract We investigated in a murine model whether UVB irradiation of lymphohemopoietic cells would prevent the development of graft-versus- host disease (GVHD). Preliminary experiments showed that spleen colony (CFU-S) formation by hemopoietic cells was preserved at UVB doses that eliminated lymphocyte proliferation. In a parent into F1 model, UVB irradiation (5 to 15 mJ/cm2) of spleen cells added to normal marrow cells prevented the development of GVHD, whereas all recipients given untreated spleen cells developed GVHD. Syngeneic recipients of marrow exposed to 2.5 to 10 mJ/cm2 of UVB achieved normal hemopoietic reconstitution. Based on these observations, B6D2 F1 (H-2b x H-2d) recipients were given 1,000 cGy of total body irradiation (TBI) followed by transplantation of 5 x 10(6) parental B6 (H-2b) bone marrow cells and 10 x 10(6) B6 spleen cells, either unirradiated or exposed to UVB before infusion. All mice transplanted with cells exposed to 10 or 12.5 mJ/cm2 of UVB survived without GVHD. At 2.5 and 5.0 mJ/cm2, mice showed signs of GVHD, beginning at day 30, and 100% and 80%, respectively, eventually developed chronic GVHD. At 7.5 mJ/cm2, mice had weight loss, from which 60% recovered and survived without GVHD, while 40% died with GVHD. At 15 mJ/cm2, some recipients died from graft failure, while some survived without GVHD. All surviving mice were complete donor-type chimeras. Spleen size and cellularity and in vitro lymphocyte responses correlated inversely with the development of GVHD. Mice without GVHD showed specific tolerance to skin grafts from the second parent strain, while animals with GVHD rejected their skin grafts. Thus, in a murine model UVB irradiation of transplanted hemopoietic stem cells allows for hemopoietic reconstitution and prevents GVHD.

Allogeneic Cytokine-Induced Killer Cell-Dependent Eimination of Host Dendritic Cells Leads to Less Graft-Versus-Host Disease.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3011-3011
Author(s):  
Shintaro Mase ◽  
Hideaki Maeba ◽  
Toshihiro Fujiki ◽  
Rie Kuroda ◽  
Raita Araki ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Nk Cells ◽  
Graft Versus Host Disease ◽  
Absolute Number ◽  
Target Cells ◽  
Host Disease ◽  
Graft Versus Host ◽  
Killing Activity ◽  
Cik Cells

Abstract Abstract 3011 Cytokine-induced killer (CIK) cells are ex vivo-expanded T lymphocytes expressing both natural killer (NK)- and T-cell markers. We have reported that adoptive transfer of allogeneic CIK cells in a murine model caused minimal graft-versus-host disease (GVHD) with retention of antitumor activity mediated by NKG2D, which is an activating receptor expressed on NK cells. The mechanism of suppression of GVHD with CIK cells is not fully understood. Host residual dendritic cells (DCs) are most important cells in initiating GVHD reaction. Therefore, we hypothesized that alloreactive NK cells, even when infused in large numbers, do not cause GVHD by killing recipient DCs with a same mechanism as CIK cells kill tumor cells. To test this, DCs generated from rodent bone marrow cells were used for 51-Cr release cytotoxicity assays as target cells. We demonstrated that though autologous CIK cells (Balb/c) had relatively strong killing activity against mature DCs (Balb/c), allogeneic CIK cells (B6) had much more killing activity even from at a 10:1 effector -target ratio as shown in Fig 1 below. In addition, killing activity against DCs did not changed with/without adding NKG2D blocking antibody, suggesting that there were possible mechanisms for cell killing other than NKG2D/NKG2D ligand system in CIK cells. To further evaluate whether allogeneic CIK cells eliminate host DCs to reduce GVHD in vivo, lethally irradiated Balb/c recipients were given BM (B6) with CIK cells or splenocytes to compare the number and activation status of residual host-typed DCs in the spleen after bone marrow transplantation. As shown in Fig 2, on day 1 after BMT absolute number of host DCs in spleen receiving splenocytes and CIK cells were almost same, however, the numbers of DCs in the mice receiving BM alone were much less. On day 3, absolute number of host DCs in all groups decreased. In particular, the number of host DCs in the mice receiving CIK cells dramatically decreased and finally reached to the same number of host DCs in the mice receiving BM alone. On the contrary, the number of host DCs in the mice receiving splenocytes didn't decrease so much and was significantly greater than number of host DCs in the mice receiving BM alone. Considering the above, when allo-CIK cells first met to DCs, both DCs and CIK cells were expanded on day 1 after BMT, and then allo-CIK cells turned to kill host DCs. In conclusion, allogeneic CIK cells caused less GVHD due in part to elimination of host DCs. Disclosures: No relevant conflicts of interest to declare.

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