IL-22 Is Critical To The Pathogenesis Of Cutaneous Gvhd Mediated By Th17 Cells

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4482-4482
Author(s):  
Hemamalini Bommiasamy ◽  
Laura Ott ◽  
Shelly West ◽  
LeShara M Fulton ◽  
Angela Panoskaltsis-Mortari ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Stem Cell ◽  
Mouse Model ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Th17 Cells ◽  
Acute Gvhd ◽  
Allogeneic Bone ◽  
Congenital Diseases

Background Allogeneic hematopoietic stem cell transplantation is used to treat a number of acquired and congenital diseases; however, a major complication of this therapy is graft versus host disease (GvHD). GvHD is a severe inflammatory disease caused by donor T cells recognizing host organs as foreign and mounting an immune response against them. Current treatment for GvHD is an immunosuppressive drug regimen that can predispose patients to opportunistic infections. Therefore, it is of critical importance to further understand the underlying mechanisms that mediate GvHD pathogenesis in efforts to develop novel therapeutic treatments. Previous work from our lab demonstrated that TH17 cells mediate severe cutaneous GvHD and that inhibiting IL-17 activity using a neutralizing anti-IL17 antibody was protective in a mouse model of skin GvHD. TH17 cells also produce the cytokine IL-22, which is known to be involved in skin inflammation resulting from psoriasis. We tested whether IL-22 from TH17 cells is also pathogenic in a mouse model of GvHD in which ex vivo polarized TH17 cells from B6 mice are transferred to lethally irradiated allogeneic B6D2 mice. Method B6D2 recipient mice were lethally irradiated with 900 cGy from a Cesium source. The following day recipient mice were given 3 x 106 T cell depleted bone marrow cells supplemented with 3-4 x 106 Th17 cells that had been polarized in vitro from fluorescence activated cell sorted CD4+/CD62Lhi T cells that had been cultured as described previously (Carlson et al Blood 2009). Recipient mice were followed for survival and scored for clinical GVHD using a standard scoring system. Additionally, recipient mice were evaluated clinically for cutaneous GVHD and scored for tissue pathology. GVHD organs were evaluated for the production of pro-inflammatory cytokines by ELISA and qPCR. Treated animals received control IgG or anti-IL-22 antibody (16mg/kg) weekly for four weeks starting on the day of transplant (Day 0). Results We found substantial expression of IL-22 mRNA in the skin of recipient mice who were transplanted with donor Th17 cells compared to those receiving naïve T cells alone (p< 0.05). When we evaluated the function of IL-22 produced by Th17 cells, we found a statistically significant decrease in cutaneous GVHD induced by Th17 cells in recipient animals treated with anti-IL-22 mAb (p< 0.05). While there was a decrease in cutaneous GVHD in the mice treated with anti-IL-22 mAb, there was no difference in overall survival or induction of GVHD outside of the cutaneous compartment. Additionally, we found increased expression of mRNA for IL-22 from a cohort of patients with late acute GVHD after allogeneic stem cell transplantation. Conclusions Unlike in the GI tract, the generation of IL-22 appears to play a pro-inflammatory role in the manifestation of cutaneous GVHD in mice after allogeneic bone marrow transplantation. High levels of mRNA for IL-22 were also found in the skin from a cohort of patients with late acute GVHD. These data suggest that targeting IL-22 may be beneficial in the treatment of cutaneous GVHD. Disclosures: Fouser: Pfizer: Employment.

Generation of Human T/NK Cell Precursors for Adoptive Transfer To Enhance Immune Reconstitution in Allogeneic Hematopoietic Stem Cell Transplantation Recipients.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3209-3209
Author(s):  
Sonali Chaudhury ◽  
Johannes Zakarzewski ◽  
Jae-Hung Shieh ◽  
Marcel van der Brink ◽  
Malcolm A.S. Moore
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem ◽  
Serum Free ◽  
Cd34 Cells

Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) is associated with significant post-transplant immunoincompetence which affects in particular the T cell lineage and results in an increased susceptibility to infections. Novel strategies to enhance immune recovery after HSCT could prevent malignant relapse and immune deficiency and improve the overall outcome of this therapy. We have established a serum free culture system using murine bone marrow stroma expressing the Notch ligand Delta-like 1 (DL1) to obtain high numbers of human pre-T cells from CD34+ cells. Human cord blood CD34+ cells were plated on OP9 DL1 stroma transduced with adenovirus expressing thrombopoietin (ad-TPO) at an MOI of 30. Media used was QBSF-60 (Serum free media prepared by Quantity Biologicals) supplemented with Flt-3 ligand and IL-7 (10ng/ml). At 4–5 weeks we obtained a 10 5–10 7 fold expansions of cultured cells of which about 70–80% were CD5, CD7 positive pre T cells (Fig 1). We then developed an optimal system to study human lymphohematopoiesis using mouse models (NOD/SCID/IL2rϒnull and NOD/SCIDβ2null) and established an adequate pre T cell number (4 × 10 6) and radiation dose (300 Rads). We injected CD34 and pre-T cells (CD45 +, CD4−, CD5+, CD7+) derived from OP9 DL1 cultures into these mice and achieved ~50%engraftment of NK in the bone marrow and spleen of the mice at 2 weeks following transplant. The thymus from the same mice showed evidence of about 12–15% CD7+ pre T cells. We are currently studying the function of the generated NK and T cells both in vivo and in vitro studies. Figure Figure

WT1-Specific Immune Responses in Patients with High-Risk Multiple Myeloma Undergoing Allogeneic T Cell-Depleted Hematopoietic Stem Cell Transplantation Followed by Donor Lymphocyte Infusions

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1993-1993 ◽  
Author(s):  
Eleanor Tyler ◽  
Achim A Jungbluth ◽  
Richard J. O'Reilly ◽  
Guenther Koehne
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Immune Responses ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematologic Malignancies ◽  
Hematopoietic Stem ◽  
Cell Responses

Abstract Abstract 1993 Wilm's tumor protein-1 (WT1) is over-expressed in a number of solid and hematologic malignancies including multiple myeloma (MM). The emergence of WT1-specific T cells has been shown to correlate with better relapse-free survival after allogeneic stem cell transplantation in patients (pts) with hematologic malignancies, such as leukemia. In MM, the expression of WT1 in the bone marrow has been shown to correlate with numerous negative prognostic factors, including disease stage and M protein ratio. Taken together, these findings suggest that immunotherapeutic augmentation of WT1-specific immune responses, such as adoptive transfer of WT1-specific T cells, may be capable of eradicating minimal residual disease and preventing relapse in MM. Thus, we examined the significance of WT1-specific cellular immune responses in pts with relapsed MM and high-risk cytogenetics who are undergoing allogeneic T cell-depleted hematopoietic stem cell transplantation (TCD HSCT). In this study, pts were eligible to receive low doses of donor lymphocyte infusions (DLI, 5×105-1×106 CD3+/kg) no earlier than 5 months post TCD HSCT. WT1-specific T-cell frequencies were measured in freshly isolated peripheral blood and bone marrow specimens. Frequencies were detected by staining for intracellular IFN-γ production in response to WT1 peptides, and/or by tetramer analysis, where available. Of 17 pts evaluated, all pts exhibited low frequencies of WT1-specific T-cell responses pre TCD HSCT. Ten of these pts received DLI post TCD HSCT. All 10 pts developed WT1-specific T cell responses post DLI. These increments in WT1-specific T-cell frequencies were associated with reduction in circulating myeloma proteins in all pts. Long-term evaluation demonstrated fluctuations in persisting WT1-specific T-cell frequencies following DLI. In one representative patient, a peak of 3.5% (72/ml) WT1-specific CD8+ T cells were detected in the peripheral blood by staining with the tetramer HLA-A*0201 RMF. This peak T-cell response occurred post TCD HSCT and DLI, and coincided with disease regression. This patient has remained in complete remission for more than 3 years post transplant, with fluctuating levels of WT1-specific CD8+ T cells ranging from 0.3–1.5% still persisting. Findings from concurrent molecular chimerism studies conducted on isolated T cells post TCD HSCT suggest that the WT1-specific T cells are of donor origin. Immunohistochemical analyses of WT1 and CD138 staining in MM bone marrow specimens demonstrated consistent co-expression within malignant plasma cells. WT1 expression in the bone marrow of all 6 pts tested correlated with the extent of malignant plasma cell infiltration. In contrast, no WT1 expression was observed when disease was low or absent. Taken together, our findings suggest a correlation between the emergence of WT1-specific T cells post DLI, and disease regression in pts being treated for relapsed MM. The present data support the development of adoptive immunotherapeutic approaches utilizing WT1-specific T cells for pts with MM. Disclosures: No relevant conflicts of interest to declare.

Refractory juvenile idiopathic arthritis: using autologous stem cell transplantation as a treatment strategy

2006 ◽  
Vol 8 (26) ◽  
pp. 1-11 ◽  
Author(s):  
Nico M. Wulffraat ◽  
Ismé M. de Kleer ◽  
Berent Prakken
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Juvenile Idiopathic Arthritis ◽  
Stem Cell Transplantation ◽  
Autoimmune Diseases ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Allogeneic Bone ◽  
Self Tolerance ◽  
A Cell

Cellular immune therapy for severe autoimmune diseases can now be considered when such patients are refractory to conventional treatment. The use of autologous stem cell transplantation (ASCT) to treat human autoimmune diseases has been initiated following promising results in a variety of animal models. Anecdotal observations have been made of autoimmune disease remission in patients who have undergone allogeneic bone marrow transplantation as a result of coincidental haematological malignancies. The possibility of inducing immunological self-tolerance by ASCT is particularly attractive as a means for treating juvenile idiopathic arthritis (JIA). In this disease, ASCT restores self-tolerance both through a cell-intrinsic mechanism, involving the reprogramming of autoreactive T cells, and through a cell-extrinsic mechanism, involving a renewal of the immune balance between CD4+CD25+ regulatory T cells and other T cells. This review describes the clinical results of ASCT performed for this disease and the possible underlying immunological mechanisms.

scholarly journals Pediatric Allogeneic Bone Marrow and Stem Cell Transplantation in Alberta, Canada † 754

1998 ◽  
Vol 43 ◽  
pp. 131-131
Author(s):  
Max J Coppes ◽  
Sunil Desai ◽  
Ronald A Anderson ◽  
Karen Booth ◽  
Johannes Wolff ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Bone Marrow ◽  
Allogeneic Bone

scholarly journals An Encouraging Successful Result of Allogeneic Hematopoietic Stem Cell Transplantation in a Boy Both with Juvenile Myelomonocytic Leukemia and Osteogenesis Imperfecta : A Case Report

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 28-28
Author(s):  
Fang Liu ◽  
Xiaofan Zhu ◽  
Wenyu Yang ◽  
Ye Guo ◽  
Xia Chen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Osteogenesis Imperfecta ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Juvenile Myelomonocytic Leukemia ◽  
Allogeneic Bone ◽  
Hematopoietic Stem ◽  
Myelomonocytic Leukemia

Background: Juvenile myelomonocytic leukemia (JMML) is a rare hematologic malignancy in young children that is classified as a myelodysplastic/myeloproliferative neoplasm and not only characterized by young age, hepatosplenomegaly, thrombocytopenia and monocytosis, but also by molecular aberrations in the RAS-RAF-MEK-ERK signaling pathway and GM-CSF-hypersensitivity. Most children with JMML experience an aggressive clinical course and the only curative treatment option for these children is stem cell transplantation (SCT). Osteogenesis imperfect (OI) is also an orphan inherited monogenic bone fragility disorder that usually is caused by mutations in one of the two genes coding for collagen type I alpha chains, COL1A1 or COL1A2. A common issue associated with the molecular abnormality is a disturbance in bone matrix synthesis and homeostasis inducing bone fragility. In very early life, this can lead to multiple fractures and progressive bone deformities. Current multidisciplinary management could only improve quality of life for patients, including physical therapy, drug treatment and orthopaedic surgery. Innovative therapies, such as progenitor and mesenchymal stem cell or bone marrow transplantation, targeting the specific altered pathway rather than the symptoms, may develop new curative treatments. Here we report a 3-year-old boy who suffered from both JMML and OI, was successfully transplanted and kept presenting an encouraging outcome up to now. Aims:To investigate the possible efficacy and safety of Allogeneic Hematopoietic Stem Cell Transplantation in a boy both with Juvenile Myelomonocytic Leukemia and Osteogenesis Imperfecta. Methods:A 3-year-old boy presented with fatigue, fever, petechia and rash in Aug 2019, accompanying with loss of appetite, joint pain and severe hepatosplenomegaly. The boy had a special appearance of short stature and blue sclerae, meanwhile he suffered intermittent eczema and bone fracture twice since he was 2 years old. Similar characteristics were also positive in his grandmother, father and father's sister. The blood cell counts revealed anemia, thrombocytopenia and leukocytosis especially monocytosis. Bone marrow aspirate showed excessive proliferation of myelomonocytic cells and hypersensitivity to granulocyte-macrophage colony-stimulating factor in vitro. Somatic mutation of gene NF1, PTPN11 and COL1A1 were identified by Next Generation Sequencing.Therefore, the little boy was diagnosed with two rare diseases of Juvenile Myelomonocytic Leukemia and Osteogenesis Imperfecta at the same time. After 4 courses of hypomethylating agents therapy, the boy underwent haploidentical allogeneic bone marrow stem cell transplantation combined with allogeneic single umbilical cord blood transplant in May 2020. The myeloablative conditioning regimen was composed of Decitabine (20mg/m2/day, days -13 to -9), Cyclophosphamide (25mg/kg/day, days -8 and -7), Busulfan(100mg/m2/day, days -6 to -3), Fludarabine (40mg/m2/day, days -6 to -2) and Cytarabine (100mg/m2/day, days -6 to -2). Post-Cyclophosphamide (50mg/kg/day, days +3 and +4), tacrolimus and mycophenolate mofetil were used for prophylaxis of graft-versus-host disease (GVHD). Results:The number of infused TNCs from haplo-bone marrow and cord blood unit was 41.4×10^8/kg and 9.72×10^7/kg, respectively, while the number of infused CD34+ cells was 11.84×10^6/kg and 2.33×10^5/kg, respectively. The boy achieved sustained engraftment of both neutrophils and platelets at 16 days and 24 days, respectively, with complete haplo-donor chimerism of confirmed at 14 days. He developed grade III acute GVHD (skin, gut and liver) and recovered at 39 days after transplant. Clinical symptoms such as rash, joint pain and hepatosplenomegaly got complete remission, and the mutated genes like NF1, PTPN11 and COL1A1 all disappeared at 30 days. At the time of this report, the boy was alive with negative MRD and good quality of life with a follow-up of 3 months after HCT. Conclusion:To our knowledge, this is the first report that a child both with Juvenile Myelomonocytic Leukemia and Osteogenesis Imperfecta was cured by allogeneic hematopoietic stem cell transplantation.Our experience suggests that allogeneic bone marrow transplantation may be a novel safe and effective therapeutic strategy for OI patients. Disclosures No relevant conflicts of interest to declare.

Gemtuzumab Ozogamicin with Donor Leucocyte Infusions Is Safe and Effective Therapy for a Subgroup of Relapsed Acute Myeloid Leukaemia and Myelodysplastic Syndrome Following Allogeneic Haemopoietic Stem Cell Transplantation (HSCT).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1806-1806 ◽  
Author(s):  
Kavita Raj ◽  
Maadh Aldouri ◽  
Aloysius Ho ◽  
Antonio Pagliuca ◽  
Stephen Devereux ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Stem Cell ◽  
Complete Remission ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Gemtuzumab Ozogamicin ◽  
Haemopoietic Stem Cell ◽  
Pre Treatment ◽  
Haemopoietic Stem Cell Transplantation

Abstract Gemtuzumab Ozogamicin (GO) is an anti-CD33 antibody linked to the cytotoxic antibiotic calicheamycin. Its use in AML and acute promyelocytic leukaemia has been previously described and its hepatotoxic side effects highlighted. Haemopoietic stem cell transplantation is another modality used in the treatment of relapsed AML with graft versus leukaemic effect being implemented by T cells that are effective against the tumor specific antigens. However relapse can occur despite the presence of 100% donor derived T cells. We report prolonged disease free survival (DFS) following the use of GO/DLI. Patients with relapsed or refractory leukaemia AML (n=28) and myelodysplasia (n=6, RAEB1 n=5, RAEB2 n=1), median age 52 yrs (19–66) received treatment with gemtuzumab ozogamicin (GO) between January 2001 and February 2004 at King’s College Hospital. Six had previously untreated AML or MDS, 17 had AML/MDS in first relapse, 4 in second relapse, 6 were refractory and 1 was in second remission. Seventeen patients received GO with FLAG ± Idarubicin and 17 had GO alone. Complete remission (CR) was similar in both groups( 47% vs. 41%respectively). Twenty seven patients received single dose, 5 patients received 2 and 2 patients received 3 doses of GO. Twenty six patients received 9mg/m2, 4 received 6mg/m2, 3 at 3mg/m2 and 1 at 4.5mg/m2. Following GO 5 patients received conventional conditioning allogeneic HSCT (AlloHSCT), 8 received reduced intensity conditioning (RIC-HSCT) and 1 had autologous rescue. HSCT was done at a median time of 37 days (17–444) post-GO. Six out of 11 patients who underwent HSCT post GO with no DLI are alive in CR, median 810d (120–1080). Hepatotoxicity with bilirubin elevation grades 2–4 (NCI toxicity criteria)occurred in 14 patients associated with elevated AST grades 2–4 in 8 patients and hepatic veno-occlusive disease in 4 patients. Pulmonary haemorrhage occurred in 3 patients, contributing to death in one. Direct anti-globulin test positivity was observed in 6 patients causing significant haemolysis in 4. Eight patients who relapsed following HSCT received GO followed by donor leucocyte infusion. Blasts from these patients were mean 75.5% (85% median)CD33+. Three of the eight patients achieved complete remission, 2 are alive 240 and 810d post GO. Two other patients underwent repeat RIC-HSCT post-GO followed by DLI, both achieved CR, and 1 is alive at 990d. Chimerism data available for 8 patients showed 0–56% donor derived haemopoiesis pre treatment. Donor derived CD3+ cells were 26%and 47% in two patients and 100% in 2 patients pre GO/DLI. In the former two patients the first did not respond to this treatment, the second became 100% donor in the unfractionated bone marrow and in CD3+ fraction. In the latter two, unfractionated bone marrow was 0% donor derived and 56% donor derived pre treatment with these increasing to 77% and a 100% donor derived respectively with the CD3+ fraction remaining 100% donor. Five of these 8 patients acheived CR.Overall 13 patients (31.4%) achieved CR, 9 (25.7%) are alive 120–1080 days post-GO, median 810d. The overall median survival post-GO was 76 days (2–1080). Our results indicate that gemtuzumab ozogamicin in combination with DLI can benefit the subgroup of patients with AML /high risk MDS who have relapsed post haemopoietic stem cell transplant.

Autologous Hematopoetic Stem Cell Transplantation as An Intensive Consolidation Therapy for Adult Patients in Remission from Acute Myeloid Leukemia.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4595-4595
Author(s):  
Sonja G Genadieva-Stavrik ◽  
Alexandra Pivkova ◽  
Zlate Stojanoski ◽  
Svetlana Krstevska-Balkanov ◽  
Borce Georgievski
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Transplantation ◽  
Allogeneic Bone ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Stem Cell Source

Abstract Abstract 4595 Despite advances in our understanding of its pathogenesis, acute myeloblastic leukemia remains difficult to treat. Although initial complete remission can be achieved in a high percentage of patients, relapse occurs in 70–80% of the patients. Two main approaches have been the attempt to eradicate the leukemic clonal cells population via chemotherapy with or without autologous stem cell rescue or to pursue a combined approach using an antileukemic therapy combined with an antileukemic immune response via allogeneic bone marrow transplantation. Autologous transplantation compares favorably against allogeneic bone marrow transplant in several ways. Autologous transplantation can be used as a consolidation therapy in the older population, and lack of a matched donor does not preclude the patients from this treatment. We report a retrospective analysis on 48 patients diagnosed with de novo AML, who did not have an available histocompatible donor, and who underwent autologous transplantation between years 2000–2009 at the University hematology Clinic, Skopje, Macedonia. All patients had ECOG score 1 or less. The patient's age ranged from 17 to 65 years with the median age 41 years. There were 26 males and 22 females. For stem cell mobilization patients received chemotherapy or chemotherapy plus G-CSF. The preparative chemotherapy regimen prior to autologous transplantation consisted of BuCy in 24 patient, BEAM in 22 and BuCyMel was used in the remaining 2 patients. We used bone marrow as primary source of stem cells in 18 patients, and peripheral blood stem cells in remaining 30 patients. The five years overall survival was 52% and the 5 years disease progression free survival were 42%. We analyzed sever factors that can influence the overall survival and the disease free survival such as: age, disease status, stem cell source, chemotherapy regiments prior to transplantation, conditioning regiments, number of mobilized stem cells. Advanced age and bone marrow stem cell source seems to be more influent factors. We report that the clinical results of autologous hematopoietic stem cell transplantation are sufficiently encouraging to warrant future trials that include autologous transplantation as an option for appropriately selected patients with AML in CR1. We conclude that autologous hematopoietic stem cell transplantation is a reasonable and save intensive consolidation for patients with acute myeloblastic leukemia who do not have a suitable HLA–matched donor. Disclosures: No relevant conflicts of interest to declare.

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