MCMV Infection Lowers the Threshold for the Development of Clinical GvHD after Allogeneic Bone Marrow Transplantation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2125-2125
Author(s):  
Mohammad S. Hossain ◽  
John D. Roback ◽  
Edmund K. Waller
Keyword(s):  
Bone Marrow ◽  
Weight Loss ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Chronic Gvhd ◽  
Viral Clearance ◽  
Allogeneic Bone ◽  
Cmv Infection ◽  
Mcmv Infection

Abstract CMV infection is reported to increase the incidence and severity of chronic GvHD and clinical data have shown that preemptive antiviral therapy decreased the risk of extensive chronic GvHD. Using mouse model of Allogeneic BMT, we investigated the mechanism for the association of MCMV infection and GvHD. We hypothesize that MCMV infection leads to generalized immune activation and increases the number of donor derived allo-reactive T cells and GvHD activity. Methods: A parenteral to F1 mouse BMT model was used to study anti-CMV immunity and GvHD. Low dose splenocytes (3x106) from MCMV immunized C57BL/6 donors (H-2b, Thy1.2+, CD45.1+) were transplanted with 5x106 T cell depleted bone marrow (TCD BM) from congeneic mice (H-2b, Thy1.1+, CD45.2+) into lethally irradiated (11Gy) CB6F1 recipients (C57BL/6 x Balb/C, H-2b/d, Thy1.2+, CD45.2+). Previous work has established this as a dose that protects against CMV without immediate lethality from GvHD. Non-GvHD control mice received a dose of Amotosalen treated splenocytes (10x106) and 5x106 TCD BM that protects against CMV without GvHD. Recipient mice were infected i.p. with a supralethal dose (2.5x104 pfu) of MCMV 7 days post transplant. Clinical GvHD was monitored twice weekly by weight loss, hair loss, ruffled fur, diarrhea, and decreased activity. T cell chimerism in recipient spleen and thymus, and MCMV peptide specific tetramer+CD8+ T cells were determined by flow cytometry. Liver and lung viral loads were determined by counting PFU in tissue homogenates plated onto 3T3 confluent monolayers. Results: During the acute phase of MCMV infection (day 3 to 14 post infection), recipient mice that received 3x106 untreated donor splenocytes developed GvHD characterized by weight loss and higher mortality than the non-GvHD control mice. Although both GvHD+ and control mice effectively cleared the virus from their liver, delayed viral clearance from the lung was found in non-GvHD recipients. Viral clearance was associated with expansion of donor spleen-derived MCMV peptide specific tetramer+ CD8+ T cells. The kinetics of donor T-cell expansion varied significantly between the two treatment groups, with GvHD+ recipients showed rapid early expansion of donor derived T-cells followed by the development of GvHD with subsequent lymphopenia. Recipients of Amotosalen-treated splenocytes had more gradual expansion of total and 400-fold expansion of antigen specific T-cells with sustained lymphoid reconstitution. GvHD+ recipients of untreated splenocytes had complete chimerism comprised of >80% of CD8+ donor T cells whereas non-GvHD controls had significant expansion of host derived T cells following MCMV infection and lacked allo-reactive of donor- spleen-derived T cells. Thymic function was inhibited among animals that developed GvHD and preserved among control mice throughout the infectious phase. Very delayed CMV infection (on day 60 after transplant) in mice with established chronic GvHD exacerbated GvHD and was associated with delayed lung viral clearance. Conclusion: After CMV infection there is extensive expansion of allo-reactive T cells in GvHD+ mice with associated damage to the microenvironment in the spleen and thymus. Amelioration of the immuno-suppressive effect of CMV infection (in clinical transplantation) will likely require more effective prophylaxis and treatment of GvHD in allotransplant recipients.

Prophylactic Amotosalen-Treated Donor T-Cells Prevent Late CMV Infection in Allogeneic Bone Marrow Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3024-3024
Author(s):  
Mohammad S. Hossain ◽  
John D. Robak ◽  
Edmund K. Waller
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Viral Infection ◽  
Cd8 T Cells ◽  
Immune Reconstitution ◽  
Chronic Gvhd ◽  
Mcmv Infection ◽  
Tnf Α ◽  
Donor T Cells ◽  
Ifn Γ

Abstract A major problem in allogeneic BMT is post transplant immunodeficiency leading to opportunistic infection and relapse. Previously we showed that amotosalen-treated allogeneic donor T cells given at the time of BMT and experimental murine cytomegalovirus (MCMV) infection could prevent lethal MCMV disease without producing GvHD. In this study we have focused on a more clinically applicable model where prophylactic amotosalen-treated allogeneic donor splenocytes are given at the time of BMT, followed by MCMV infection 100 days later. We observed that amotosalen-treated donor T-cells significantly expanded and responded well in presence of viral infection without inducing any GvHD, protected recipients against viral disease, and were associated with significantly improved hematopoietic engraftment and immune reconstitution. Methods: Using a parent to F1 mouse BMT model, splenocytes (3x106 untreated or 10x106 amotosalen-treated) from MCMV immunized C57BL/6 donors were transplanted along with 5x106 T-cell depleted bone marrow (TCD BM) from naïve congeneic mice into lethally irradiated (11Gy) CB6F1 recipients (C57BL/6 x Balb/C). Recipient mice were infected i.p. with a sublethal dose (5x104 pfu per mouse) of MCMV 100 days or more after transplant. Clinical chronic GvHD was monitored by weight loss, hair loss, ruffled fur, diarrhea, and decreased activity. Flow cytometry was used to quantitate T cell chimerism (in recipient PBMC, spleen, liver and thymus) and MCMV-peptide specific CD8+ T-cells (tetramer+ and IFN-γ producing). Serum IFN-γ and TNF-α were determined by ELISA. Liver and spleen viral loads were determined by counting PFU in tissue homogenates plated onto 3T3 confluent monolayers. Results: Recipients of untreated control donor splenocytes suffered from chronic GvHD within 100 days of transplant, while those that received amotosalen-treated splenocytes experienced no GvHD. In response to MCMV infection at 100 days post transplant, residual amotosalen-treated donor T-cells rapidly expanded over 25-fold within 10 days, but did not cause lethality or detectable GvHD. Expanded amotosalen-treated T-cells showed activated anti-viral responses and developed a memory phenotype at late phases of viral infection. PBMC, spleen and liver showed elevated levels of MCMV specific tetramer+, IFN-γ+, and TNF-α+ CD8+ T-cells that were associated with accelerated viral clearance within day 3 after viral infection. While expansion and generation of amotosalen-treated donor T-cells mostly occurred in the liver, the generation of donor bone marrow-derived new T-cells occurred through both the thymus and the liver. In contrast, recipients of untreated donor splenocytes had reduced thymic function, resulting in severely impaired immune reconstitution and decreased anti-viral immunity. Conclusion: Prophylactically administered amotosalen-treated allogeneic donor T cells 1) were almost completely devoid of GvHD activity, 2) promoted hematopoietic engraftment and improved immune reconstitution, and 3) persisted long-term (>100 days) and successfully protected recipients from sublethal MCMV infection. Thus, infusion of amotosalen-treated donor T-cells at the time of transplantation is a clinically-attractive approach to adoptive anti-viral immunotherapy without chronic GvHD following hematopoietic progenitor cell transplantation.

scholarly journals Donor Leukocyte Infusions Are Effective in Relapsed Multiple Myeloma After Allogeneic Bone Marrow Transplantation

Blood ◽  
1997 ◽  
Vol 90 (10) ◽  
pp. 4206-4211 ◽  
Author(s):  
H.M. Lokhorst ◽  
A. Schattenberg ◽  
J.J. Cornelissen ◽  
L.L.M. Thomas ◽  
L.F. Verdonck
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
T Cells ◽  
Prognostic Factors ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Marrow Transplantation ◽  
Chronic Gvhd ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone

Abstract Donor leukocyte infusions (DLI) can induce sustained remissions in patients with acute and chronic myeloid leukemia who relapse after allogeneic bone marrow transplantation (allo-BMT). Also, in multiple myeloma (MM), incidental reports have indicated the existence of a graft-versus-myeloma effect (GVM) induced by allo-reactive T cells. We performed a retrospective study in a larger group of MM patients to characterize better the effect, prognostic factors, and toxicity of this new treatment modality. Thirteen patients with relapsed MM after allo-BMT were studied. Patients received a total of 29 DLI with T-cell doses ranging from 1 × 106/kg to 33 × 107/kg. Repetitive courses, sometimes with escalated cell doses, were undertaken in case of no response to or relapse after DLI. Eight of 13 patients responded: 4 patients achieved a partial remission and 4 patients achieved a complete remission. Dose escalation was effective in 3 patients. The time to response was median 6 weeks (range, 4 to 10 weeks). Major toxicities were secondary to acute and chronic graft-versus-host disease (GVHD), which occurred in 66% and 56% of all patients and in 87% and 85% of the responders, respectively. Two responding patients developed fatal BM aplasia. The only prognostic factors for response were a T-cell dose greater than 1 × 108/kg and the occurrence of GVHD. Seven of nine patients developing acute GVHD responded, as compared with only 1 response in the 4 patients without GVHD and 6 of 7 patients with chronic GVHD responded, whereas no response was observed in the 5 patients without chronic GVHD. DLI are effective in a high percentage of patients with relapsed MM after allo-BMT, although it is associated with a high treatment-related toxicity. The dose of T cells used may be important in determining the GVM effect, with the highest probability of response after infusion of more than 1 × 108 T cells. Because the optimal individual dose may vary, patient-adapted therapy consisting of repeated infusions with escalating dose of donor leukocytes until maximum response is achieved may therefore be preferable.

scholarly journals Differential effects of donor T-cell cytokines on outcome with continuous bortezomib administration after allogeneic bone marrow transplantation

Blood ◽  
2008 ◽  
Vol 112 (4) ◽  
pp. 1522-1529 ◽  
Author(s):  
Kai Sun ◽  
Minghui Li ◽  
Thomas J. Sayers ◽  
Lisbeth A. Welniak ◽  
William J. Murphy
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Cd8 T Cells ◽  
Marrow Transplantation ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone Marrow ◽  
T Cell Subsets ◽  
Allogeneic Bone

Abstract Dissociating graft-versus-tumor (GVT) effect from acute graft-versus-host disease (GVHD) still remains a great challenge in allogeneic bone marrow transplantation (allo-BMT). Bortezomib, a proteasome inhibitor, has shown impressive efficacy as a single agent in patients with hematologic malignancies but can result in toxicity when administered late after allogeneic transplantation in murine models of GVHD. In the current study, the effects of T-cell subsets and their associated cytokines on the efficacy of bortezomib in murine allogeneic BMT were investigated. Increased levels of serum tumor necrosis factor-α (TNFα) and interferon-γ (IFNγ) were observed after allo-BMT and continuous bortezomib administration. Bortezomib-induced GVHD-dependent mortality was preventable by depletion of CD4+ but not CD8+ T cells from the donor graft. The improved survival correlated with markedly reduced serum TNFα but not IFNγ levels. Transfer of Tnf−/− T cells also protected recipients from bortezomib-induced GVHD-dependent toxicity. Importantly, prolonged administration of bortezomib after transplantation of purified CD8+ T cells resulted in enhanced GVT response, which was dependent on donor CD8+ T cell–derived IFNγ. These results indicate that decreased toxicity and increased efficacy of bortezomib in murine allo-BMT can be achieved by removal of CD4+ T cells from the graft or by inhibiting TNFα.

Interleukin-15 enhances immune reconstitution after allogeneic bone marrow transplantation

Blood ◽  
2005 ◽  
Vol 105 (2) ◽  
pp. 865-873 ◽  
Author(s):  
Onder Alpdogan ◽  
Jeffrey M. Eng ◽  
Stephanie J. Muriglan ◽  
Lucy M. Willis ◽  
Vanessa M. Hubbard ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Cd8 T Cells ◽  
Marrow Transplantation ◽  
Immune Reconstitution ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Interleukin 15

AbstractInterleukin-15 (IL-15) is a γ-common cytokine that plays an important role in the development, survival, and proliferation of natural killer (NK), NK T, and CD8+ T-cells. We administered IL-15 to recipients of an allogeneic bone marrow transplantation (allo BMT) to determine its effects on immune reconstitution. Posttransplantation IL-15 administration significantly increased donor-derived CD8+ T (mostly CD122+CD44+CD8+ T-cells), NK, and NK T-cells at day +28 in young and old recipients of allo BMT. This was associated with enhanced T-cell and NK-cell function. IL-15 stimulated homeostatic proliferation of donor CD8+ T-cells in recipients of carboxyfluorescein diacetate succinimidyl ester–labeled donor T-cell infusions. Posttransplantation IL-15 administration also resulted in a decrease in apoptotic CD8+ T-cells, an increase in Bcl-2–expressing CD8+ T-cells, and an increase in the fraction of Ki67+ proliferative NK and CD8+ T-cells in recipients of allo BMT. IL-15 did not exacerbate graft-versus-host disease (GVHD) in recipients of T-cell–depleted BMT but could aggravate GVHD in some cases in recipients of a T-cell–repleted BMT. Finally, we found that IL-15 administration could enhance graft-versus-leukemia activity. In conclusion, IL-15 can be administered safely to recipients of a T-cell–depleted allo BMT to enhance CD8+ T, NK, and NK T-cell reconstitution.

Recipient Langerhans Cells Are Neither Required Nor Sufficient for GVHD Induction in MHC-Matched Allogeneic BMT, but a Langerin+ Cell Is a Pivotal Regulator of Langerhans Cell Turnover Post Transplantation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3511-3511
Author(s):  
Hongmei Li ◽  
Daniel Kaplan ◽  
Anthony Jake Demetris ◽  
Jennifer McNiff ◽  
Mark Shlomchik ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Weight Loss ◽  
T Cells ◽  
T Cell ◽  
Bone Marrow Transplant ◽  
T Cell Activation ◽  
Langerhans Cells ◽  
Marrow Transplant ◽  
Allogeneic Bone ◽  
Donor T Cells

Abstract Graft-versus-host disease (GVHD) is initiated when alloreactive donor T cells are primed by professional antigen-presenting cells (APCs) to undergo clonal expansion and maturation. Host APCs that survive pretransplant conditioning play an essential role in this T cell activation, and are an attractive target for GVHD prevention and treatment. However, APCs are diverse in phenotype, location and function and an understanding of the roles of distinct subsets is an important first step in developing APC-targeted therapies. Skin is the most frequently affected organ in GVHD. Langerhans cells (LCs), characterized by expression of Langerin, are a major APC in the epidermis, and thus it was logical to hypothesize that host LCs would have a role in GVHD induction. Indeed, in an MHC-mismatched model, Merad et al. showed that host LCs persist after T cell-depleted (TCD) but not T cell-replete bone marrow transplant (BMT), and that these host LCs in donor→host chimeras are sufficient to induce skin GVHD after a second allogeneic bone marrow transplant (alloBMT). However, this work did not examine the role of recipient LCs when all other APCs are intact, the scenario at the time of transplant in all patients. To address this question, we created a transgenic mouse that constitutively lacks epidermal LCs. We did so by expressing diphtheria toxin A chain (DTA) driven by the human Langerin gene (Kaplan, et al 2005) in a bacterial artificial chromosome (BAC). We used Langerin-DTA BAC transgene positive (Tg+) mice or Tg-littermates as recipients in the C3H.SW (H-2b)→B6 (H-2b) strain paring, in which recipient APCs are necessary and sufficient for GVHD induction. Tg+ and Tg− CD8 recipients developed similar GVHD as measured by weight loss and clinical skin disease. Tg+ and Tg− CD8 recipients also had comparable pathologic GVHD of the skin, ear, liver and colon. To generalize these findings, we used B6bm12 →B6 strain pairing, an MHCII-mismatched CD4-dependent GVHD model, in which recipient APCs are also required (Teshima et al, 2002). Tg+ and Tg− CD4 recipients developed similar weight loss and pathologic changes in the tongue and liver, primary sites of GVHD in this model. Thus, in both MHC-matched and MHC-mismatched models in which recipient APCs are absolutely required, the specific absence of recipient epidermal LCs did not affect clinical or histological GVHD. We also analyzed LC turnover in these alloBMT recipients. As previously reported, LCs remained host-derived in B6 Tg− recipients of TCD C3H.SW bone marrow. Given our prior result that C3H.SW → B6 chimeras are resistant to GVHD induction by a second alloBMT from C3H. SW donors (Shlomchik, et al 1999), unlike in the MHC-mismatched model employed by Merad, residual host LCs are insufficient to initiate GVHD in this MHC-matched system. In B6 Tg− recipients of TCD C3H.SW bone marrow plus GVHD-inducing CD8 cells, LC turnover varied by mouse and ranged from all host or donor to a mix of donor and host LCs. This variability could relate to the extent of skin GVHD, as we previously found that epidermal MHCII+ cells in skin GVHD lesions in this model are donor-derived (Matte et all, 2004). Strikingly, in contrast to Tg− recipients, donor-derived LCs developed in Tg+ recipients of TCD C3H.SW bone marrow. Donor LCs also engrafted in Tg+ recipients of TCD bone marrow from Tg− but otherwise syngeneic littermates or B6 RAG1−/− T cell-deficient donors. Thus, in contrast to LC-replete mice, neither allogeneic donor T cells nor UV-induced inflammation was required for donor LC engraftment in LC-deficient hosts. These data indicate that a Langerin+ cell, absent in Langerin-DTA Tg+ mice, regulates LC turnover in the absence of inflammation. Work is underway to identify this key cell.

An Essential Role for STAT1 Signaling in Regulation of Donor CD4+ T Cell Dependent Acute Graft Versus Host Disease (GVHD) Following Allogeneic Bone Marrow Transplantation (BMT).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3551-3551
Author(s):  
Huihui Ma ◽  
Caisheng Lu ◽  
Judith Ziegler ◽  
Suzanne Lentzsch ◽  
Markus Y. Mapara
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Research Funding ◽  
Allogeneic Bone Marrow Transplantation ◽  
Treg Cells ◽  
Allogeneic Bone ◽  
Target Tissue

Abstract Abstract 3551 Poster Board III-488 We have previously demonstrated that activation of STAT1 and STAT3 in target tissue and secondary lymphoid organs belong to the earliest events during induction of GVHD. Using STAT1-gene-deficient (STAT1KO) mice we tested the role of donor STAT1 in fully MHC-mismatched (129Sv[H2b] to BALB/c [H2d]) and MHC-matched minor histocompatibility antigen (mHA)-mismatched strain combinations (129Sv[H2b] to B6[H2b]). GVHD was induced lethal irradiation and transplantation of allogeneic donor bone marrow cells and whole spleen cells. GVHD in the MHC-mismatched model is primarily CD4 dependent. Induction of GVHD was associated with activation of STAT1 and significant expansion of activated STAT1 expressing CD4+ and CD8+ T cells as assessed by analysis of STAT1 Tyr701 phosphorylation using phosphoflow staining. Using STAT1KO whole splenocytes we were able to show that lack of STAT1 significantly inhibited development of GVHD in both major and mHA mismatched recipients with significantly extended median survival times (MST) and lower GVHD morbidity. Protection against GVHD in recipients of STAT1KO splenocytes was associated with significant contraction of CD8+ T cells, but expansion of CD4 T cells on days +3 and +6 post-BMT in the MHC-mismatched setting. Most importantly, we observed a significant expansion of CD4+CD25+ FOXP3+ Treg cells in recipients of STAT1KO splenocytes. Lack of STAT1 in donor splenocytes resulted in a significantly attenuated and skewed systemic inflammatory response on day +6 post-BMT as demonstrated by significantly reduced IFN-g levels 508pg/ml vs 84.pg/ml (p<0.05), but significantly increased IL-4 (p=0.003), IL-5 (p=0.007) and IL-17 (p=0.03) levels. IL-6 levels were also increased with a trend towards statistical significance (p=0.08). In vitro studies demonstrated that STAT1KO CD8+ T cells produced much less IFN-g upon combined engagement of TCR and costimulation, but that this decrease in IFN-g secretion could be rescued if cells were simultaneously cultured under Th1 conditions (ie in the presence of IL-12 and anti-IL4 antibody). In contrast, lack of STAT1 completely inhibited the differentiation of naïve CD4+ T cells to IFN-g -producing cells upon TCR commitment and this capacity was also severely impaired under Th1 conditions. Furthermore, we observed a significantly reduced number of CXCR3−expressing CD4+ T cells in recipients of STAT1 KO splenocytes. In parallel to the afore-mentioned observations, tissue samples from BMT mice on day +3 and day +6 showed significantly less inflammation in liver and gut in recipients of STAT1 KO splenocytes compared to wild type cells. These data indicate that donor STAT1 is important for the induction of acute GVHD and that attenuation of GVHD in the absence of STAT1 involves expansion of Treg cells, perturbation of T cell polarization and subsequent reduced expression of the chemokine receptor CXCR3 on donor T cells leading to impaired target organ infiltration. Disclosures: Lentzsch: Celgene: Consultancy, Research Funding; cephalon: Consultancy, Research Funding. Mapara:Genzyme: Membership on an entity's Board of Directors or advisory committees; Resolvyx: Consultancy, Honoraria, Research Funding; Gentium: Stock Ownership.

scholarly journals Outcome of alloanergized haploidentical bone marrow transplantation after ex vivo costimulatory blockade: results of 2 phase 1 studies

Blood ◽  
2008 ◽  
Vol 112 (6) ◽  
pp. 2232-2241 ◽  
Author(s):  
Jeff K. Davies ◽  
John G. Gribben ◽  
Lisa L. Brennan ◽  
Dongin Yuk ◽  
Lee M. Nadler ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Marrow Transplantation ◽  
Viral Infections ◽  
Ex Vivo ◽  
Chronic Gvhd ◽  
Costimulatory Blockade ◽  
Donor T Cells

AbstractWe report the outcomes of 24 patients with high-risk hematologic malignancies or bone marrow failure (BMF) who received haploidentical bone marrow transplantation (BMT) after ex vivo induction of alloantigen-specific anergy in donor T cells by allostimulation in the presence of costimulatory blockade. Ninety-five percent of evaluable patients engrafted and achieved full donor chimerism. Despite receiving a median T-cell dose of 29 ×106/kg, only 5 of 21 evaluable patients developed grade C (n = 4) or D (n = 1) acute graft-versus-host disease (GVHD), with only one attributable death. Twelve patients died from treatment-related mortality (TRM). Patients reconstituted T-cell subsets and immunoglobulin levels rapidly with evidence of in vivo expansion of pathogen-specific T cells in the early posttransplantation period. Five patients reactivated cytomegalovirus (CMV), only one of whom required extended antiviral treatment. No deaths were attributable to CMV or other viral infections. Only 1 of 12 evaluable patients developed chronic GVHD. Eight patients survive disease-free with normal performance scores (median follow-up, 7 years). Thus, despite significant early TRM, ex vivo alloanergization can support administration of large numbers of haploidentical donor T cells, resulting in rapid immune reconstitution with very few viral infections. Surviving patients have excellent performance status and a low rate of chronic GVHD.

scholarly journals Keratinocyte growth factor enhances DNA plasmid tumor vaccine responses after murine allogeneic bone marrow transplantation

Blood ◽  
2009 ◽  
Vol 113 (7) ◽  
pp. 1574-1580 ◽  
Author(s):  
Robert R. Jenq ◽  
Christopher G. King ◽  
Christine Volk ◽  
David Suh ◽  
Odette M. Smith ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Keratinocyte Growth Factor ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Effector Cells ◽  
Cd8 Cells ◽  
T Cell Reconstitution ◽  
Dna Plasmid

Abstract Keratinocyte growth factor (KGF), which is given exogenously to allogeneic bone marrow transplantation (allo-BMT) recipients, supports thymic epithelial cells and increases thymic output of naive T cells. Here, we demonstrate that this improved T-cell reconstitution leads to enhanced responses to DNA plasmid tumor vaccination. Tumor-bearing mice treated with KGF and DNA vaccination have improved long-term survival and decreased tumor burden after allo-BMT. When assayed before vaccination, KGF-treated allo-BMT recipients have increased numbers of peripheral T cells, including CD8+ T cells with vaccine-recognition potential. In response to vaccination, KGF-treated allo-BMT recipients, compared with control subjects, generate increased numbers of tumor-specific CD8+ cells, as well as increased numbers of CD8+ cells producing interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). We also found unanticipated benefits to antitumor immunity with the administration of KGF. KGF-treated allo-BMT recipients have an improved ratio of T effector cells to regulatory T cells, a larger fraction of effector cells that display a central memory phenotype, and effector cells that are derived from a broader T-cell–receptor repertoire. In conclusion, our data suggest that KGF can function as a potent vaccine adjuvant after allo-BMT through its effects on posttransplantation T-cell reconstitution.

scholarly journals Partial restoration of immune response in Hepatitis C patients after viral clearance by direct-acting antiviral therapy

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0254243
Author(s):  
Meritxell Llorens-Revull ◽  
Maria Isabel Costafreda ◽  
Angie Rico ◽  
Mercedes Guerrero-Murillo ◽  
Maria Eugenia Soria ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Hepatitis C ◽  
T Cell ◽  
Cd8 T Cells ◽  
Viral Clearance ◽  
Cd4 T Cell ◽  
Care Hospital ◽  
T Cell Exhaustion ◽  
Cell Exhaustion

Background & aims HCV CD4+ and CD8+ specific T cells responses are functionally impaired during chronic hepatitis C infection. DAAs therapies eradicate HCV infection in more than 95% of treated patients. However, the impact of HCV elimination on immune responses remain controversial. Here, we aimed to investigate whether HCV cure by DAAs could reverse the impaired immune response to HCV. Methods We analyzed 27 chronic HCV infected patients undergoing DAA treatment in tertiary care hospital, and we determined the phenotypical and functional changes in both HCV CD8+ and CD4+ specific T-cells before and after viral clearance. PD-1, TIM-3 and LAG-3 cell-surface expression was assessed by flow cytometry to determine CD4+ T cell exhaustion. Functional responses to HCV were analyzed by IFN-Ɣ ELISPOT, intracellular cytokine staining (IL-2 and IFN-Ɣ) and CFSE-based proliferation assays. Results We observed a significant decrease in the expression of PD-1 in CD4+ T-cells after 12 weeks of viral clearance in non-cirrhotic patients (p = 0.033) and in treatment-naive patients (p = 0.010), indicating a partial CD4 phenotype restoration. IFN-Ɣ and IL-2 cytokines production by HCV-specific CD4+ and CD8+ T cells remained impaired upon HCV eradication. Finally, a significant increase of the proliferation capacity of both HCV CD4+ and CD8+ specific T-cells was observed after HCV elimination by DAAs therapies. Conclusions Our results show that in chronically infected patients HCV elimination by DAA treatment lead to partial reversion of CD4+ T cell exhaustion. Moreover, proliferative capacity of HCV-specific CD4+ and CD8+ T cells is recovered after DAA’s therapies.

scholarly journals Itolizumab As a Potential Therapeutic for the Prevention and Treatment of Graft Vs Host Disease

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5603-5603 ◽  
Author(s):  
Cherie Tracy Ng ◽  
Jeanette Ampudia ◽  
Robert J. Soiffer ◽  
Jerome Ritz ◽  
Stephen Connelly
Keyword(s):  
Weight Loss ◽  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Vehicle Control ◽  
Control Group ◽  
Employment Equity ◽  
Equity Ownership

Background: CD6 is a co-stimulatory receptor, predominantly expressed on T cells, that binds to activated leukocyte cell adhesion molecule (ALCAM), a ligand expressed on antigen presentation cells and various epithelial and endothelial tissues. The CD6-ALCAM pathway plays an integral role in modulating T cell activation, proliferation, differentiation and trafficking and is central to inflammation. While effector T cell (Teff) are CD6hi and upregulate expression upon activation, regulatory T cells (Treg) remain CD6lo/-, making this an attractive target to modulate Teff activity while preserving Treg activity. Early studies by Soiffer and colleagues demonstrated using T12, an anti-CD6 monoclonal antibody (mAb) that ex-vivo depletion of CD6+ donor cells prior to transplantation decreased the incidence of both acute and chronic GVHD, highlighting the importance of CD6+ cells in GVHD pathogenesis and validating it as a therapeutic target. However, it remains to be shown whether modulating the CD6-ALCAM pathway in vivo can attenuate GVHD. We investigated the use of itolizumab, a humanized anti-CD6 mAb that has demonstrated clinical efficacy in other autoimmune diseases, as both a preventive and therapeutic treatment for GVHD, using a humanized xenograft mouse model. Methods: Humanized xenograft mice were generated by intravenous transfer of 2x10^7 human PBMCs into 6-8 weeks old NOD/SCID IL2rγ-null (NSG). To investigate the ability of itolizumab to prevent GVHD, mice were dosed with either 60μg or 300μg of itolizumab, 150μg of abatacept (CTLA4-Ig), or vehicle, starting one day prior to PBMC transplantation. To investigate the therapeutic effect of itolizumab, mice were dosed with either 150μg of itolizumab or vehicle, starting at Day 5 post-PBMC transfer, when transplanted T cells are already activated. All treatments were administered IP every other day. Weight and disease scores were monitored throughout the study. At Days 18 and 35, peripheral blood was evaluated by flow cytometry to examine T cell prevalence, and tissues were collected for histological examination of pathology and T cell infiltration. Results: When administered as prevention (Day -1), treatment with either 60μg or 300μg of itolizumab significantly decreased mortality compared to the vehicle control (100% vs. 10%); this decrease was similar to the positive control group treated with abatacept (Figure 1). At 60μg, itolizumab-treated mice demonstrated significant reductions in the prevalence of human T cells in peripheral blood vs. vehicle-treated mice at Day 18 (<0.2% vs. 74.5%; p < 0.001). The reduction in peripheral T cells was accompanied by reductions in tissue-infiltrating T cells in lung (85-fold) and gut (9.5-fold), as well as reductions in disease scores and weight loss. When administered therapeutically, treatment with itolizumab was associated with a survival rate of 50% compared to 10% in the control group (Figure 2). Similarly, peripheral T cell prevalence (34.3% vs. 65.1%; p < 0.001), weight loss, and disease scores were inhibited by itolizumab compared to vehicle control mice. Conclusions: These data suggest that systemic treatment with itolizumab can modulate pathogenic Teff cell activity, establishing this antibody as a potential therapeutic for patents with GvHD. A phase I/II study using itolizumab as first line treatment in combination with steroids for patients with aGVHD is currently ongoing (NCT03763318). Disclosures Ng: Equillium: Employment, Equity Ownership. Ampudia:Equillium: Employment. Soiffer:Mana therapeutic: Consultancy; Kiadis: Other: supervisory board; Gilead, Mana therapeutic, Cugene, Jazz: Consultancy; Juno, kiadis: Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Cugene: Consultancy; Jazz: Consultancy. Ritz:Equillium: Research Funding; Merck: Research Funding; Avrobio: Consultancy; TScan Therapeutics: Consultancy; Talaris Therapeutics: Consultancy; Draper Labs: Consultancy; LifeVault Bio: Consultancy; Celgene: Consultancy; Aleta Biotherapeutics: Consultancy; Kite Pharma: Research Funding. Connelly:Equillium: Employment, Equity Ownership.

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