Donor cell-derived hematological malignancy: a survey by the Japan Society for Hematopoietic Cell Transplantation

Leukemia ◽  
2016 ◽  
Vol 30 (8) ◽  
pp. 1742-1745 ◽  
Author(s):  
M Kato ◽  
T Yamashita ◽  
R Suzuki ◽  
K Matsumoto ◽  
H Nishimori ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Hematological Malignancy ◽  
Donor Cell ◽  
Hematopoietic Cell ◽  
Japan Society

scholarly journals Animal Models for Preclinical Development of Allogeneic Hematopoietic Cell Transplantation

ILAR Journal ◽  
2018 ◽  
Vol 59 (3) ◽  
pp. 263-275
Author(s):  
Scott S Graves ◽  
Maura H Parker ◽  
Rainer Storb
Keyword(s):  
Animal Models ◽  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Hematopoietic Cell Transplantation ◽  
Donor Cell ◽  
Hematopoietic Cell ◽  
Disease Relapse ◽  
Preclinical Development ◽  
Host Disease ◽  
Graft Versus Host

Abstract Since its inception in the 1950s, hematopoietic cell transplantation (HCT) has become a highly effective clinical treatment for malignant and nonmalignant hematological disorders. This milestone in cancer therapy was only possible through decades of intensive research using murine and canine animal models that overcame what appeared in the early days to be insurmountable obstacles. Conditioning protocols for tumor ablation and immunosuppression of the recipient using irradiation and chemotherapeutic drugs were developed in mouse and dog models as well as postgrafting immunosuppression methods essential for dependable donor cell engraftment. The random-bred canine was particularly important in defining the role of histocompatibility barriers and the development of the nonmyeloablative transplantation procedure, making HCT available to elderly patients with comorbidities. Two complications limit the success of HCT: disease relapse and graft versus host disease. Studies in both mice and dogs have made significant progress toward reducing and to some degree eliminating patient morbidity and mortality associated with both disease relapse and graft versus host disease. However, more investigation is needed to make HCT more effective, safer, and available as a treatment modality for other non-life-threatening diseases such as autoimmune disorders. Here, we focus our review on the contributions made by both the murine and canine models for the successful past and future development of HCT.

scholarly journals CD26 inhibition enhances allogeneic donor-cell homing and engraftment after in utero hematopoietic-cell transplantation

Blood ◽  
2006 ◽  
Vol 108 (13) ◽  
pp. 4268-4274 ◽  
Author(s):  
William H. Peranteau ◽  
Masayuki Endo ◽  
Obinna O. Adibe ◽  
Aziz Merchant ◽  
Philip W. Zoltick ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Donor Cell ◽  
In Utero ◽  
Hematopoietic Cell ◽  
Cell Homing ◽  
Donor Chimerism ◽  
Donor Cells ◽  
Donor Specific Tolerance ◽  
Specific Tolerance

Abstract In utero hematopoietic-cell transplantation (IUHCT) can induce donor-specific tolerance to facilitate postnatal transplantation. Induction of tolerance requires a threshold level of mixed hematopoietic chimerism. CD26 is a peptidase whose inhibition increases homing and engraftment of hematopoietic cells in postnatal transplantation. We hypothesized that CD26 inhibition would increase donor-cell homing to the fetal liver (FL) and improve allogeneic engraftment following IUHCT. To evaluate this hypothesis, B6GFP bone marrow (BM) or enriched hematopoietic stem cells (HSCs) were transplanted into allogeneic fetal mice with or without CD26 inhibition. Recipients were analyzed for FL homing and peripheral-blood chimerism from 4 to 28 weeks of life. We found that CD26 inhibition of donor cells results in (1) increased homing of allogeneic BM and HSCs to the FL, (2) an increased number of injected animals with evidence of postnatal engraftment, (3) increased donor chimerism levels following IUHCT, and (4) a competitive engraftment advantage over noninhibited congenic donor cells. This study supports CD26 inhibition as a potential method to increase the level of FL homing and engraftment following IUHCT. The resulting increased donor chimerism suggests that CD26 inhibition may in the future be used as a method of increasing donor-specific tolerance following IUHCT.

Acute Gvhd Induced by In Utero Hematopoietic Cell Transplantation Is Reversed by a Regulatory Response Resulting in a Potent Graft Vs. Hematopoietic Effect without Clinical Gvhd

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1904-1904
Author(s):  
Miho Watanabe ◽  
Jesse Vrecenak ◽  
Jacqueline Tsai ◽  
Jason Sulkowski ◽  
Edem Timpo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Cell Transplantation ◽  
Clinical Evidence ◽  
Hematopoietic Cell Transplantation ◽  
Bone Marrow Cells ◽  
Donor Cell ◽  
Hematopoietic Cell ◽  
Cell Populations ◽  
Target Organs

Abstract Abstract 1904 Introduction: In Utero Hematopoietic Cell Transplantation (IUHCT) is a potential treatment for congenital hematologic disorders. The rationale is to utilize normal events during hematopoietic and immunologic development to facilitate hematopoietic engraftment. While the risk of graft versus host disease (GVHD) after IUHCT would be anticipated to be high, based on Medawar's tenets, surprisingly little GVHD has been observed after experimental IUHCT and IUHCT induced GVHD has not been previously characterized. To better understand the potential risk of IUHCT induced GVHD prior to clinical application, we attempted to intentionally induce GVHD pathophysiology in the allogeneic murine model of IUHCT. Methods: Bone marrow (BM) cells (10×106) from C57/BL6 (B6, H2kb, GFP−) mice were co-injected with increasing doses of splenocytes from B6-GFP (H2kb, GFP+) mice intravenously into Balb/c (H2kd) fetuses at embryonic day 14 (E14). Control groups included: 1) 10×106 B6 BM cells alone; 2) same doses of B6-GFP splenocytes alone; and 3) IUHCT of congenic donor cell populations into B6 recipients. Surviving pups were assessed using a clinical GVHD scale and separate cohorts were harvested at pre- and post-natal time-points for analysis by fluorescence stereoscopic microscopy (FSM), flow cytometry for assessment of donor and host cell populations in hematopoietic tissues, and histologic assessment of target tissues for GVHD. Results: Prenatal Analysis - In the allogenic groups that received 10×106 BM cells plus increasing doses of splenocytes (0.1×106 to 10×106 splenocytes/fetus) a consistent distribution of GFP positive cells could be seen by whole body FSM in lymphohematopoietic sites (spleen, lymph nodes, thymus and fetal liver) at E16 that did not differ significantly from congenic controls. By E19 – E20 however, marked proliferation of the cells occurred with clear infiltration of GVHD target organs (skin, lungs, liver, intestine). This expansion was proportionate to the dose of splenocytes and was not seen in congenic or BM only controls. Increased mortality was not observed until doses greater than 5 × 106 splenocytes were given (approx. 5 × 1011 splenocytes/kg est. fetal wt.) with perinatal death likely attributable to respiratory insufficiency. Postnatal Analysis - In the allogeneic groups there was minimal clinical evidence of GVHD up to and inclusive of the 5×106 splenocyte dose. A few pups showed poor growth relative to the normal growth curve and mild fur ruffling, but these resolved by P15, and there was no further clinical evidence of GVHD and no postnatal deaths up to P60. In harvested tissues many GFP+ cells persisted in GVHD target organs, however, no GVHD histopathology was observed at any time. Flow cytometric analysis confirmed a proliferation of donor splenocytes that peaked around P5-P10. Lymphocyte subset analysis revealed an expansion of predominantly CD8+ T-cells. Alkaline phosphatase in the host liver, as a marker of GVHD was increased during the same time course and returned to normal by P15. An increase of host and donor BM derived CD4+ cells was also observed that peaked around P15-17. Further analysis confirmed an increase in both T-regulatory cells and activated CD4+ T-cells compared to normal or BM only controls. The most remarkable observation was a dramatic graft versus hematopoietic (GVH) effect with an increase in donor BM derived chimerism at P60 to > 80% with no clinical GVHD. These findings were seen only in the allogenic group that received both splenocytes and bone marrow cells, not in the other groups. In the group that received only bone marrow cells, the chimerism remained at low levels (Figure 1). Conclusion: Our data demonstrates that the fetus is in fact resistant to GVHD relative to myeloablated postnatal BMT recipients. While there is an aggressive alloimmune activation and expansion of donor T-cells, clinical manifestations are mild and are reversed by what appears to be a T-regulatory cell expansion. In our model, the alloimmune activation phase is accompanied by a potent GVH response providing a competitive advantage for donor cells and resulting in marked enhancement of donor cell engraftment without clinical evidence of GVHD. Further work in this model is directed toward defining regulatory and effector mechanisms involved in controlling GVHD and the GVH effect. Disclosures: No relevant conflicts of interest to declare.

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