scholarly journals Intestinal Epithelial HIF-2 Is Protective in Gut Graft-Versus-Host-Disease

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1865-1865
Author(s):  
Rena Feinman ◽  
Iriana Colorado ◽  
Keyi Wang ◽  
Eugenia Dziopa ◽  
Leah Dziopa ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
T Cell ◽  
Immune Responses ◽  
Intestinal Inflammation ◽  
Intestinal Stem Cell ◽  
Intestinal Epithelial ◽  
Adaptive Immune Responses ◽  
Graft Versus Host ◽  
Adaptive Immune

Abstract The failure to control both innate and adaptive immune responses in the gut has recently been implicated as a major pathogenic mechanism in the development of graft-versus-host disease (GVHD). Reduced oxygen availability in the intestine has been causally linked to gastrointestinal disease. During intestinal inflammation, increased metabolic activity of resident and infiltrating immune cells, bacteria and reduced blood flow may lead to a sharp decrease of oxygen, resulting in "inflammatory" hypoxia. The transcription factor family, hypoxia-inducible factor (HIF) originally discovered as a master regulator of the adaptive response to hypoxia, has recently emerged as a key regulator of the innate and adaptive immune responses. The HIF heterodimer consists of an oxygen-labile α subunit (HIFα) and a constitutively expressed HIF-1β subunit. Both HIF-1α and HIF-2α expression are markedly elevated in intestinal epithelial cells of patients with inflammatory bowel disease (IBD) and intestinal epithelial HIF-1 attenuates colitis in preclinical mouse models. Although HIF-2 has not been studied extensively in intestinal inflammation, it has emerged as a key regulator in intestinal iron homeostasis. Given that IBD and GVHD share many pathogenic mechanisms, we hypothesized that a sustained HIF response will protect the host intestinal epithelium from conditioning- and alloreactive T cell-induced gut damage. To determine the functional significance of intestinal epithelial HIF-1 and HIF-2 in gut GVHD, we generated conditional intestinal epithelial HIF-1α (HIF-1αΔIE) and HIF-2αΔIE vil-cre knockout (KO) mice on a C57BL/6 (B6) background lacking HIF-1α or HIF-2α in the host intestinal epithelium. Using a fully MHC mismatched B10.BR (H2k)→B6 (H2b) bone marrow transplant (BMT) model, loss of intestinal epithelial HIF-2 reduced the median survival time (43d) compared to wild-type (WT) recipients (58d, log-rank test, P < 0.005). Although intestinal epithelial HIF-1 deficiency shortened the median survival time (48.5d), it did not reach statistical difference. Loss of intestinal epithelial HIF-1 or HIF-2 worsened GVHD-induced histopathologic crypt damage compared to WT mice transplanted with T cell depleted bone marrow (BM) and enriched T cells (BM+T), 8d post- BMT. Pronounced subepithelial lifting, mucosal edema and sloughing were more evident in the villus tips of HIF-2αΔIE mice than HIF-1αΔIE mice. Hyperplastic crypts that are characteristic of regenerating crypts after radiation-induced damage were observed in Ki67-stained ileal/jejunal sections of WT mice post-BMT whereas fewer regenerating Ki67-labeled crypts were found in both HIF-1αΔIE and HIF-2αΔIE mice. In control T cell depleted BM groups (WT, HIF-1αΔIE and HIF-2αΔIE), Ki67+ -proliferating cells resided at the crypt base. Using quantitative real-time PCR analysis, we determined whether intestinal epithelial HIF-1 and HIF-2 differentially regulated the expression of Paneth cells and intestinal stem cell markers in the jejunum, 8d post-BMT. A 5-fold and 2-fold decrease in lysozyme (Lyz) mRNA levels occurred in WT (p<0.001) and HIF-1αΔIE BM+T mice (p<0.001) compared to their respective BM groups, 8d post-BMT. However, due to a 2-fold decrease in endogenous Lyz expression in HIF-1αΔIE (p<0.01) and HIF-2αΔIE (p<0.001) BM mice compared to WT BM mice, Lyz levels were not differentially changed among BM+T groups. Loss of either intestinal epithelial HIF-1 or HIF-2 reduced Reg3γ (p<0.05) and Sox9 (p<0.01) levels whereas only epithelial HIF-1 deficiency reduced Hes-1 by 2-fold (p<0.001) and prevented the recovery of the Lgr5 levels (p<0.01) compared to WT BM+T mice. In summary, we found that both intestinal epithelial HIF-1 and HIF-2 may protect the intestinal stem cell niche from GVHD-induced injury. Importantly, our results suggest that intestinal epithelial HIF-2 may be necessary in preventing GVHD-induced mortality. Disclosures No relevant conflicts of interest to declare.

Allogeneic Mesenchymal Stem Cells Can Mitigate Early, Ongoing, and Severe Graft Versus Host Disease but Require Delayed Administration for Optimal Effect.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 594-594 ◽  
Author(s):  
D. Polchert ◽  
J. Sobinsky ◽  
M. Kidd ◽  
A. Moadsiri ◽  
E. Reina ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Immune Responses ◽  
Graft Versus Host Disease ◽  
Optimal Timing ◽  
Graft Versus Host ◽  
Donor T Cells

Abstract Mesecnhymal stem cells have been observed to inhibit graft versus host disease clinically, however the timing of infusion of these cells has not been well characterized. In previous studies, we have observed MSC to rescue lethally irradiated hosts that had received sub-optimal numbers of stem cells, permit the reduction of host conditioning while establishing equal or better levels of engraftment than the combination of intensive host conditioning and untreated HSC grafts, and enable xenogeneic engraftment (rat→ mouse) suggesting that administration of MSC in combination with an allogeneic transplant significantly alters host immune responses to enhance engraftment.. These findings could only be observed if MSC were given on the same day as the bone marrow stem cells. The purpose of this study was to determine to what extent MSC might affect donor immune responses involved in GVHD and to determine the optimal timing of these effects, in order to optimize the maximal beneficial effects of allogeneic stem cell grafts engineered with MSC. Since GVHD, mediated by donor T cells, requires host antigen presentation for initiation, we tested whether the effect of MSC occurred before or after this interaction. We used an established GVHD model in which 20x 10^6 Balb/c bone marrow cells in combination with 15 x 10^6 Balb/c splenocytes were administered to lethally irradiated B6 recipients to test whether MSC (1.0 x 105) could inhibit initiation of GVHD and to what extent these cells could mitigate or abrogate ongoing GVHD. In control animals, we observed donor T cell expansion to occur in the absence of B6 host T cells with corresponding destructive effects resulting in 100% lethality by day 48. Four experimental groups (n=10 per group) were used to test MSC administration at 4 time points: 1) on day 0 following co-culture with the graft to test whether cell contact between MSC and GVHD-producing splenocytes is necessary, 2) on day 2 to test whether donor T cell exposure to host antigen is required, 3) on day 20, to test the magnitude of effect of MSC on ongoing GVHD, and 4) on day 30 in which GVHD is severe and usually irreversible. Mice were weighed twice weekly and monitored daily for survival and clinical evidence of GVHD (ruffled fur, cachexia, alopecia, and diarrhea). When compared to survival of control animals, no statistically significant effect was observed when MSC were given with the stem cell grafts on day 0. Strikingly, survival was significantly increased to 60% when given on day 2 (p=0.01, log rank test), to 50% when given on day 20 (p=0.005), and to 40% for day 30 treated animals (p=0.009). Following MSC infusion, those animals that developed signs of GVHD such as ruffled fur and alopecia had dramatic improvement of these physical findings with most surviving animals experiencing a complete reversal to normal appearing fur. The observation that no effect occurred with MSC administered at the time of bone marrow transplantation suggests that the mechanism of effect requires host antigen presentation. We conclude that optimal timing for the infusion of donor specific MSC to abrogate GVHD begins after donor T cells have encountered host antigen and can be equally effective during early, late, and severe GVHD. Clinical strategies involving the use of allogeneic stem cell grafts engineered with MSC are likely to be more powerful in overcoming GVHD if the MSC infusion is administered in a delayed fashion.

An animal model of adult T-cell leukemia: humanized mice with HTLV-1–specific immunity

Blood ◽  
2014 ◽  
Vol 123 (3) ◽  
pp. 346-355 ◽  
Author(s):  
Kenta Tezuka ◽  
Runze Xun ◽  
Mami Tei ◽  
Takaharu Ueno ◽  
Masakazu Tanaka ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Animal Model ◽  
Immune Responses ◽  
Humanized Mice ◽  
Cell Leukemia ◽  
Adaptive Immune Responses ◽  
Hematopoietic Stem ◽  
Adult T Cell Leukemia ◽  
Adaptive Immune ◽  
Key Points

Key Points Humanized mice, IBMI-huNOG, were generated by intra–bone marrow injection of human CD133+ hematopoietic stem cells. HTLV-1–infected IBMI-huNOG mice recapitulated distinct ATL-like symptoms as well as HTLV-1–specific adaptive immune responses.

scholarly journals A Comprehensive Review and Update on the Pathogenesis of Inflammatory Bowel Disease

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Qingdong Guan
Keyword(s):  
Inflammatory Bowel Disease ◽  
Immune Responses ◽  
Bowel Disease ◽  
Genetic Factors ◽  
Intestinal Inflammation ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Host Genetic ◽  
Inflammatory Bowel ◽  
Host Genetic Factors

Inflammatory bowel disease (IBD) is a chronic and life-threating inflammatory disease of gastroenteric tissue characterized by episodes of intestinal inflammation. The pathogenesis of IBD is complex. Recent studies have greatly improved our knowledge of the pathophysiology of IBD, leading to great advances in the treatment as well as diagnosis of IBD. In this review, we have systemically reviewed the pathogenesis of IBD and highlighted recent advances in host genetic factors, gut microbiota, and environmental factors and, especially, in abnormal innate and adaptive immune responses and their interactions, which may hold the keys to identify novel predictive or prognostic biomarkers and develop new therapies.

scholarly journals S892 INTESTINAL STEM CELL DAMAGE IN GRAFT-VERSUS-HOST DISEASE IS PRIMARILY CAUSED BY T-CELL DERIVED INTERFERON-GAMMA

HemaSphere ◽  
2019 ◽  
Vol 3 (S1) ◽  
pp. 401-402
Author(s):  
S.A. Jansen ◽  
S. Takashima ◽  
M.L. Martin ◽  
Y.-Y. Fu ◽  
J. Bos ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Interferon Gamma ◽  
Graft Versus Host Disease ◽  
Cell Damage ◽  
Intestinal Stem Cell ◽  
Host Disease ◽  
Graft Versus Host

Graft-Versus-Host Tolerance in Dogs Following T-Cell Depleted Bone Marrow Transplantation with Absorbed ATG or CD6-Antibody.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2338-2338
Author(s):  
Julia Zorn ◽  
Hans Jochem Kolb
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Stem Cell ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Nk Cells ◽  
Marrow Transplantation ◽  
Graft Versus Host ◽  
Host Tolerance ◽  
Rabbit Complement

Abstract Graft-versus-host disease (GvHD) is the major obstacle of allogeneic stem cell transplantation. Depletion of T-cells from the graft reduces the risk of GvHD, but results in a higher risk of leukemia relapse. Adoptive immunotherapy with donor lymphocyte transfusion (DLT) has been shown to control leukemia in patients after T-cell depleted allogeneic stem cell transplantation. However, GvHD may occur, if DLT is given too early after transplantation. In canine models of DLA-identical and DLA-haploidentical bone marrow transplantation, we compared different methods of T-cell depletion (TCD) and investigated the potential of DLT at different times after transplantation to induce GvHD. T-cell depletion was performed either with absorbed anti-thymocyte globuline (aATG) or with a combination of CD6-antibody and baby rabbit complement. ATG was absorbed with erythrocytes, liver, kidney and spleen for eliminating antibodies against stem cells. CD6-antibody (M-T606) and rabbit complement depleted T-cells effectively without affecting hematopoietic progenitor cells. Unlike aATG, monoclonal CD6-antibody spares natural killer (NK) cells and some CD8-positive cells. Treatment of bone marrow with aATG prevented GvHD in 9 dogs following DLA-identical transplantation. DLT on days 1 and 2 or 21 and 22 induced fatal GvHD in two dogs each. However, it did not induce GvHD when given on days 61 and 62 and later. In DLA-haploidentical bone marrow recipients, non-manipulated marrow produced fatal GvHD in all dogs (n=7), whereas marrow treated with aATG (vol:vol 1:100 and 1:200) produced fatal GvHD in 5 out of 16 dogs only. CD6-depletion prevented GvHD in 3 of 3 DLA-haploidentically transplanted dogs. DLT produced fatal GvHD in one dog each, when given on day 3, 7 or 14 after CD6-depleted haploidentical bone marrow transplantation. However, it produced fatal GvHD in only 2 of 4 dogs transfused on day 20 post grafting. Thus, DLT could be given earlier in DLA-haploidentical animals transplanted with CD6-depleted marrow than in DLA-identical animals transplanted with aATG treated marrow without producing GvHD. These findings support the hypothesis that graft-versus-host tolerance can be induced earlier with grafts not depleted of NK cells. NK cells in the graft may inactivate host dendritic cells necessary for the induction of GvHD. In grafts depleted with aATG, NK cells are depleted as well, because aATG still retains broad specificity despite extensive absorptions. This leaves host DCs unaffected. Transfused donor T-cells encountering this environment will thus be activated which results in severe GvHD. In contrast, monoclonal CD6-antibody spares NK cells, so that donor lymphocytes cannot be activated by host DCs at the time of DLT and thus won’t trigger GvHD. CD6-depletion is the preferred method if adoptive immunotherapy with DLT is planned.

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.

scholarly journals The immunoreceptor adapter protein DAP12 suppresses B lymphocyte–driven adaptive immune responses

2011 ◽  
Vol 208 (8) ◽  
pp. 1661-1671 ◽  
Author(s):  
Takako Nakano-Yokomizo ◽  
Satoko Tahara-Hanaoka ◽  
Chigusa Nakahashi-Oda ◽  
Tsukasa Nabekura ◽  
Nadia K. Tchao ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Immune Responses ◽  
B Cell ◽  
Genetic Disorder ◽  
Elevated Serum ◽  
Sh2 Domain ◽  
Adapter Protein ◽  
Adaptive Immune Responses ◽  
Adaptive Immune

DAP12, an immunoreceptor tyrosine-based activation motif–bearing adapter protein, is involved in innate immunity mediated by natural killer cells and myeloid cells. We show that DAP12-deficient mouse B cells and B cells from a patient with Nasu-Hakola disease, a recessive genetic disorder resulting from loss of DAP12, showed enhanced proliferation after stimulation with anti-IgM or CpG. Myeloid-associated immunoglobulin-like receptor (MAIR) II (Cd300d) is a DAP12-associated immune receptor. Like DAP12-deficient B cells, MAIR-II–deficient B cells were hyperresponsive. Expression of a chimeric receptor composed of the MAIR-II extracellular domain directly coupled to DAP12 into the DAP12-deficient or MAIR-II–deficient B cells suppressed B cell receptor (BCR)–mediated proliferation. The chimeric MAIR-II–DAP12 receptor recruited the SH2 domain–containing protein tyrosine phosphatase 1 (SHP-1) after BCR stimulation. DAP12-deficient mice showed elevated serum antibodies against self-antigens and enhanced humoral immune responses against T cell–dependent and T cell–independent antigens. Thus, DAP12-coupled MAIR-II negatively regulates B cell–mediated adaptive immune responses.

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