Daratumumab Prevents Experimental Xenogeneic Graft-Versus-Host Disease by Skewing Proportions of T Cell Functional Subsets and Inhibiting T Cell Activation and Migration

Graft-versus-host disease (GVHD) remains the major cause of mortality and morbidity in non-relapse patients after allogeneic hematopoietic cell transplantation (allo-HCT). As the number of patients undergoing allo-HCT increases, it will become imperative to determine safe and effective treatment options for patients with GVHD, especially those who become refractory to systemic steroid therapy. Daratumumab (Dara), a humanized IgG1 (ĸ subclass) monoclonal antibody targeting the CD38 epitope, is used for the treatment of multiple myeloma. CD38 is a multifunctional ectoenzyme that behaves either as an enzyme, a cell adhesion molecule or a cell surface receptor involved in cell signaling. CD38 is also expressed on various immune effector and suppressor cells. However, the role of CD38 in the immune response remains elusive. We questioned whether CD38 is a potential therapeutic target against alloreactive T cells in the GVHD pathological process. Here, we investigated the impact of Dara on xenogeneic GVHD (xeno-GVHD) and graft-versus-leukemia (GVL) effects in a humanized murine model of transplantation, where human peripheral blood mononuclear cells were adoptively transplanted into immunocompromised NOD.SCID.gc-null (NSG) mice. Mice receiving Dara treatment experienced less weight loss, longer survival and lower GVHD scores compared with those in the control group. Histological evaluations, flow cytometry, RNA-sequencing and RT-qPCR analysis revealed that Dara efficaciously mitigated GVHD through multiple mechanisms including inhibition of the proliferation, activation and differentiation of CD8+ cytotoxic T cells, reduced expression of cytotoxic effector molecules, pro-inflammatory cytokines, chemokines and chemoattractant receptors by T cells and promotion of immunosuppressive T cells. More importantly, Dara preserved the GVL effect in a humanized mouse model of leukemia by metabolic reprograming of T cells to promote the induction of Th17, Th1/17and Tc1/17 cells. Our findings indicate that Dara may be an attractive therapeutic option to separate GVHD from GVL effects in patients with hematopoietic malignancies receiving allo-HCT.

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Inhibition of HIF Prolyl Hydroxylases Mitigate Gut Graft-Versus-Host Disease

Blood ◽

10.1182/blood.v128.22.3349.3349 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3349-3349

Author(s):

Rena Feinman ◽

Iriana Colorado ◽

Keyi Wang ◽

Eugenia Dziopa ◽

Michael A Flynn ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

T Cell ◽

Graft Versus Host Disease ◽

Therapeutic Potential ◽

Paneth Cell ◽

Control Group ◽

High Power Field ◽

Host Disease ◽

Graft Versus Host

Abstract The etiology of graft-versus-host disease (GVHD) is rooted in the alloreactive response of donor T cells present in the hematopoietic graft resulting in the destruction of the patient's tissues, particularly the gastrointestinal tract. Gut GVHD affects up to 50% of patients, is a leading cause of death, and has overlapping features with inflammatory bowel disease (IBD). Increased gut permeability, alterations of the gut microbiome and intestinal stem cell niche damage predispose the gut to the local and systemic effects of GVHD, and is exacerbated by the inability of the gut to adequately regenerate. Severe shifts in metabolism and reduced oxygen (O2) availability in the inflamed gut are major underlying factors in the pathogenesis of IBD. Two related transcription factors, hypoxia-inducible factor-1 (HIF-1) and HIF-2, originally discovered as master regulators of the adaptive response to hypoxia, have been recently shown to be gut protective and promote mucosal healing in response to injury. Using a MHC mismatched B10.BR→B6 bone marrow transplant (BMT) model, we previously found that loss of intestinal epithelial (IE) HIF-1α or HIF-2α worsened survival compared to wild-type mice and exhibited increased GVHD-induced-histopathology. Thus, we hypothesized that HIF-1 and HIF-2 protects and repairs the gut from conditioning and GVHD-related damage. HIF-1 and HIF-2 are heterodimers consisting of an O2-labile HIF-1α or HIF-2α subunit respectively and a constitutively expressed HIF-1β subunit. The recent discovery that iron-dependent prolyl hydroxylase enzymes (PHD1-3) can trigger the O2-dependent proteasomal degradation of the HIF-1α subunit has led to the development of pan-PHD inhibitors (PHDi) that activate HIF-1 and HIF-2. PHDi such as dimethyloxallyl glycine (DMOG) and AKB-4924 have been shown to attenuate colitis and radiation-induced gut toxicity in animal models. We thus sought to determine whether PHDi could also ameliorate gut GVHD in the B10.BR→B6 BMT model. B6 mice were lethally irradiated (10Gy, split dose) and transplanted with 5x106 T-cell depleted bone marrow (BM) cells from B10.BR donors with 2x106 enriched T cells from spleens and lymph nodes (BM+T). B6 mice transplanted with only T cell depleted BM cells served as our non-GVHD control group. B6 mice were treated with AKB-4924 (AKB, 5 mg/kg) or vehicle (β-cyclodextrin) via intraperitoneal delivery, beginning 1 day prior to BMT and for 6 consecutive days post-BMT. Treatment with AKB prevented significant weight loss, compared to vehicle-treated mice, 7 days post-BMT (n=6, p<.002). Histopathologic assessment of the jejunum of AKB treated mice after 7 days revealed fewer apoptotic cells and an increased number of Paneth and goblet cells compared to vehicle-treated mice. Immunohistochemical staining for lysozyme showed that AKB prevented GVHD-induced Paneth cell ablation compared to their vehicle BMT counterpart (2.8 Lyz+ cells/crypt vs 0.84 Lyz+ cells/crypt, n=3, p<.003). Additionally, we evaluated the effects of AKB on T cell alloreactivity. In mixed lymphocyte reaction Elispot assays, AKB and DMOG, reduced the alloreactive interferon (IFN)-γ response in B10.BR anti-B6 (p<0.001) and MHC matched, minor antigen-mismatched B6 anti-BALB.B cultures (p<0.05). Furthermore, AKB reduced the number of gut-infiltrating CD3+ T cells compared to vehicle-treated BMT mice (39 vs 155.1 CD3+ cells/high-power field, n=3, p<.0003). Our results provide the framework to validate the therapeutic potential of PHDi as an intestinal regenerative strategy in mitigating GVHD. Disclosures Peters: Aerpio Therapeutics: Employment, Equity Ownership.

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Influence of T-cell depletion on chronic graft-versus-host disease: results of a multicenter randomized trial in unrelated marrow donor transplantation

Blood ◽

10.1182/blood-2005-04-1614 ◽

2005 ◽

Vol 106 (9) ◽

pp. 3308-3313 ◽

Cited By ~ 77

Author(s):

Steven Z. Pavletic ◽

Shelly L. Carter ◽

Nancy A. Kernan ◽

Jean Henslee-Downey ◽

Adam M. Mendizabal ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Graft Versus Host Disease ◽

Conditioning Regimen ◽

Cell Depletion ◽

Unrelated Donor ◽

T Cell Depletion ◽

Host Disease ◽

Graft Versus Host ◽

The Impact

AbstractDonor-derived T cells have been proposed to play a role in pathogenesis of chronic graft-versus-host disease (cGVHD). The impact of ex vivo T-cell depletion (TCD) on cGVHD was analyzed in a randomized multicenter trial involving unrelated donor marrow transplants. A total of 404 patients diagnosed with hematologic malignancies received a total body irradiation-based myeloablative conditioning regimen. GVHD prophylaxis included TCD plus cyclosporine (CSA) or unmodified grafts with CSA plus methotrexate (M/C). Median recipient age was 31.2 years (range, 0.5-55.6 years); median follow-up time since randomization was 4.2 years. The mean number of T cells infused was 1 log lower on the TCD arm. The incidence of cGVHD at 2 years was similar between the TCD and M/C arms, 29% versus 34% (P = .27), respectively. Survival at 3 years from diagnosis of cGVHD was also similar, (TCD 51% versus M/C 58%; P = .29). The proportion of patients with cGVHD who discontinued immunosuppression at 5 years was not different (TCD 72% versus M/C 63%; P = .27), and incidence of serious infections and leukemia relapse were similar on both treatment arms. In spite of a significant reduction of acute GVHD, TCD did not reduce the incidence of cGVHD or improve survival in patients who developed cGVHD.

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CCR1 Expression on Donor Leukocytes Is Critical to the Development of Graft Versus Host Disease after Allogeneic SCT.

Blood ◽

10.1182/blood.v104.11.3067.3067 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3067-3067

Author(s):

Gerhard C. Hildebrandt ◽

Sung Choi ◽

Krystyna M. Olkiewicz ◽

Stephen W. Chensue ◽

Chen Liu ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Graft Versus Host Disease ◽

T Cell Responses ◽

Target Organ ◽

Host Disease ◽

Graft Versus Host ◽

Cell Responses ◽

Donor Cells ◽

The Impact

Abstract Acute graft versus host disease (aGVHD) is the major complication of allogeneic stem cell transplantation (allo-SCT) and limits the utility of this treatment strategy. The pathophysiology of aGVHD involves injury to host tissues by inflammatory cytokines and donor-derived cellular effectors, the recruitment of which is likely mediated by chemokine receptor: ligand interactions. CCR1 is expressed on various cell types such as T cells, monocytes and macrophages and binds to a group of CC chemokines that includes RANTES (CCL5) and Mip-1a (CCL3). In light of the previously described role for both donor T cells and monocytes in the development of aGVHD, we tested the hypothesis that CCR1 expression on donor leukocytes contributes to systemic and target organ inflammation that occurs in this setting by using a well established murine SCT model (B6→B6D2F1) and mutant mice deficient in CCR1. Lethally (1100cGy) irradiated B6D2F1 mice received SCT either from syngeneic (B6D2F1) or allogeneic (B6) CCR1+/+ or CCR1−/− donors. The severity of GVHD was assessed after SCT by survival and a clinical scoring system that incorporates changes in weight loss, fur texture, skin integrity, mobility and posture. As expected, syngeneic SCT recipients all survived and where indistinguishable from naïve, untransplanted controls, whereas animals receiving allo-SCT from CCR1+/+ donors developed significant GVHD and only 50% of animals survived by day 35. By contrast, allo-SCT with CCR1−/− donor cells resulted in significantly improved survival (92% vs. 50%) and less severe clinical GVHD (1.0±0.3 vs. 3.0±0.5) compared to allo-CCR1+/+ controls. In addition, serum TNFa levels were significantly decreased by day +7 following CCR1−/− SCT (4.7±2.7 vs. 55.3±14.4 pg/ml) and correlated with a significant reduction in intestinal histopathology both on day 7 (16.3±1.0 vs. 21.5±0.9) and on day 14 (15.8±1.8 vs. 23.8±1.0). GVHD injury to liver and skin was mild at these time points and did not differ between allo groups. Next we investigated the impact of CCR1 expression on allo-specific T cell responses in vivo and found that by day +7 after SCT both splenic T cell expansion (3.7±0.4 vs. 9.6±0.9 x 106 cells) and serum IFNγ levels (4561±559 vs. 10028±681 pg/ml) were significantly lower when CCR1 was absent on donor cells. In summary, we describe a heretofore unknown role for CCR1 on donor leukocytes in the development of aGVHD. The improvement in systemic and target organ disease observed after CCR1−/− SCT may be attributed to 1) alterations in leukocyte recruitment to the intestinal tract resulting in improved intestinal integrity, reduced translocation of endotoxin and decreased TNFa production and 2) modulation of donor T cell responses to host allo-antigens. Experiments are ongoing to determine whether strategies targeting CCR1 signalling can be exploited to prevent GVHD but maintain GVL effects and thereby improve overall survival after allo-SCT.

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Aberrant regulation of superantigen responses during T-cell reconstitution and graft-versus-host disease in immunodeficient mice

Blood ◽

10.1182/blood.v100.6.2216.h81802002216_2216_2224 ◽

2002 ◽

Vol 100 (6) ◽

pp. 2216-2224

Author(s):

David Spaner ◽

Xiaofang Sheng-Tanner ◽

Andre C. Schuh

Keyword(s):

T Cells ◽

T Cell ◽

Graft Versus Host Disease ◽

Adoptive Transfer ◽

Scid Mice ◽

Control Mechanisms ◽

Activated T Cells ◽

Host Disease ◽

Immunodeficient Mice ◽

Graft Versus Host

Acute graft-versus-host disease (GVHD) after allogeneic stem cell transplantation is associated with impaired deletion and anergy of host-reactive T cells. To elucidate the immunoregulatory events that may contribute to such dysregulated T-cell responses in GVHD, we studied superantigen (SAg) responses after adoptive T-cell transfer into severe combined immunodeficient (SCID) mice. SAg responses are normally regulated by mechanisms involving deletion and anergy, with SAg-reactive T cells typically being deleted rapidly in vivo. In a SCID mouse model of GVHD, however, allogeneic host SAg-reactive T cells were not deleted rapidly, but rather persisted in increased numbers for several months. Moreover, depending on the timing of SAg stimulation and the numbers of T cells transferred, dysregulation (impaired deletion and anergy) of SAg responses could be demonstrated following the adoptive transfer of syngeneic T cells into SCID mice as well. Transgenic T-cell receptor-bearing KJ1-26.1+ T cells were then used to determine the fate of weakly reactive T cells after adoptive transfer and SAg stimulation. When transferred alone, KJ1-26.1+ T cells demonstrated impaired deletion and anergy. In the presence of more strongly staphylococcal enterotoxin B (SEB)–reactive T cells, however, KJ1-26.1+ T cells were regulated normally, in a manner that could be prevented by inhibiting the effects of more strongly SEB-reactive cells or by increasing the level of activation of the KJ1-26.1+ T cells themselves. We suggest that the control mechanisms that normally regulate strongly activated T cells in immunocompetent animals are lost following adoptive transfer into immunodeficient hosts, and that this impairment contributes to the development of GVHD.

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A combination of anti-CD3 and anti-CD7 ricin A-immunotoxins for the in vivo treatment of acute graft versus host disease

Blood ◽

10.1182/blood.v95.12.3693 ◽

2000 ◽

Vol 95 (12) ◽

pp. 3693-3701 ◽

Cited By ~ 26

Author(s):

Ypke V. J. M. van Oosterhout ◽

Liesbeth van Emst ◽

Anton V. M. B. Schattenberg ◽

Wil J. M. Tax ◽

Dirk J. Ruiter ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Nk Cells ◽

Graft Versus Host Disease ◽

T Cell Response ◽

Cytotoxic T Cell ◽

Host Disease ◽

Graft Versus Host ◽

Ricin A

Abstract This study evaluated the anti-graft versus host disease (GVHD) potential of a combination of immunotoxins (IT), consisting of a murine CD3 (SPV-T3a) and CD7 (WT1) monoclonal antibody both conjugated to deglycosylated ricin A. In vitro efficacy data demonstrated that these IT act synergistically, resulting in an approximately 99% elimination of activated T cells at 10−8 mol/L (about 1.8 μg/mL). Because most natural killer (NK) cells are CD7+, NK activity was inhibited as well. Apart from the killing mediated by ricin A, binding of SPV-T3a by itself impaired in vitro cytotoxic T-cell cytotoxicity. Flow cytometric analysis revealed that this was due to both modulation of the CD3/T-cell receptor complex and activation-induced cell death. These results warranted evaluation of the IT combination in patients with refractory acute GVHD in an ongoing pilot study. So far, 4 patients have been treated with 3 to 4 infusions of 2 or 4 mg/m2 IT combination, administered intravenously at 48-hour intervals. The T1/2 was 6.7 hours, and peak serum levels ranged from 258 to 3210 ng/mL. Drug-associated side effects were restricted to limited edema, fever, and a modest rise of creatine kinase levels. One patient developed low-titer antibodies against ricin A. Infusions were associated with an immediate drop of circulating T cells, followed by a more gradual but continuing elimination of T/NK cells. One patient mounted an extensive CD8 T-cell response directly after treatment, not accompanied with aggravating GVHD. Two patients showed nearly complete remission of GVHD, despite unresponsiveness to the extensive pretreatment. These findings justify further investigation of the IT combination for treatment of diseases mediated by T cells.

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Prevention of Transfusion-Associated Graft-Versus-Host Disease by Photochemical Treatment

Blood ◽

10.1182/blood.v93.9.3140 ◽

1999 ◽

Vol 93 (9) ◽

pp. 3140-3147 ◽

Cited By ~ 100

Author(s):

Joshua A. Grass ◽

Tamim Wafa ◽

Aaron Reames ◽

David Wages ◽

Laurence Corash ◽

...

Keyword(s):

T Cells ◽

Gamma Radiation ◽

Graft Versus Host Disease ◽

Clinical Signs ◽

Peripheral Blood Cell ◽

Control Group ◽

Host Disease ◽

Graft Versus Host

Abstract Photochemical treatment (PCT) with the psoralen S-59 and long wavelength ultraviolet light (UVA) inactivates high titers of contaminating viruses, bacteria, and leukocytes in human platelet concentrates. The present study evaluated the efficacy of PCT to prevent transfusion-associated graft-versus-host disease (TA-GVHD) in vivo using a well-characterized parent to F1 murine transfusion model. Recipient mice in four treatment groups were transfused with 108 splenic leukocytes. (1) Control group mice received syngeneic splenic leukocyte transfusions; (2) GVHD group mice received untreated allogeneic splenic leukocytes; (3) gamma radiation group mice received gamma irradiated (2,500 cGy) allogeneic splenic leukocytes; and (4) PCT group mice received allogeneic splenic leukocytes treated with 150 μmol/L S-59 and 2.1 J/cm2UVA. Multiple biological and clinical parameters were used to monitor the development of TA-GVHD in recipient mice over a 10-week posttransfusion observation period: peripheral blood cell levels, spleen size, engraftment by donor T cells, thymic cellularity, clinical signs of TA-GVHD (weight loss, activity, posture, fur texture, skin integrity), and histologic lesions of liver, spleen, bone marrow, and skin. Mice in the control group remained healthy and free of detectable disease. Mice in the GVHD group developed clinical and histological lesions of TA-GVHD, including pancytopenia, marked splenomegaly, wasting, engraftment with donor derived T cells, and thymic hypoplasia. In contrast, mice transfused with splenic leukocytes treated with (2,500 cGy) gamma radiation or 150 μmol/L S-59 and 2.1 J/cm2 UVA remained healthy and did not develop detectable TA-GVHD. Using an in vitro T-cell proliferation assay, greater than 105.1 murine T cells were inactivated by PCT. Therefore, in addition to inactivating high levels of pathogenic viruses and bacteria in PC, these data indicate that PCT is an effective alternative to gamma irradiation for prevention of TA-GVHD.

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Signaling Through the Type 2 Cannabinoid Receptor Regulates the Severity of Acute and Chronic Graft versus Host Disease

Blood ◽

10.1182/blood.2020004871 ◽

2020 ◽

Author(s):

Cheng Yin Yuan ◽

Vivian Zhou ◽

Garrett Sauber ◽

Todd M Stollenwerk ◽

Richard Komorowski ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Graft Versus Host Disease ◽

Cd8 T Cells ◽

Acute Gvhd ◽

Cannabinoid Receptor ◽

Therapeutic Targeting ◽

Host Disease ◽

Graft Versus Host

Graft versus host disease (GVHD) pathophysiology is a complex interplay between cells that comprise the adaptive and innate arms of the immune system. Effective prophylactic strategies are therefore contingent upon approaches that address contributions from both immune cell compartments. In the current study, we examined the role of the type 2 cannabinoid receptor (CB2R) which is expressed on nearly all immune cells and demonstrated that absence of the CB2R on donor CD4+ or CD8+ T cells, or administration of a selective CB2R pharmacological antagonist, exacerbated acute GVHD lethality. This was accompanied primarily by the expansion of proinflammatory CD8+ T cells indicating that constitutive CB2R expression on T cells preferentially regulated CD8+ T cell alloreactivity. Using a novel CB2R-EGFP reporter mouse, we observed significant loss of CB2R expression on T cells, but not macrophages, during acute GVHD, indicative of differential alterations in receptor expression under inflammatory conditions. Therapeutic targeting of the CB2R with the agonists, tetrahydrocannabinol (THC) and JWH-133, revealed that only THC mitigated lethal T cell-mediated acute GVHD. Conversely, only JWH-133 was effective in a sclerodermatous chronic GVHD model where macrophages contribute to disease biology. In vitro, both THC and JWH-133 induced arrestin recruitment and ERK phosphorylation via CB2R, but THC had no effect on CB2R-mediated inhibition of adenylyl cyclase. These studies demonstrate that the CB2R plays a critical role in the regulation of GVHD and suggest that effective therapeutic targeting is dependent upon agonist signaling characteristics and receptor selectivity in conjunction with the composition of pathogenic immune effector cells.

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Immunohistology and immunocytology of human T-cell chimerism and graft- versus-host disease in SCID mice

Blood ◽

10.1182/blood.v81.12.3440.3440 ◽

1993 ◽

Vol 81 (12) ◽

pp. 3440-3448 ◽

Cited By ~ 54

Author(s):

G Hoffmann-Fezer ◽

C Gall ◽

U Zengerle ◽

B Kranz ◽

S Thierfelder

Keyword(s):

T Cells ◽

T Cell ◽

T Lymphocyte ◽

Graft Versus Host Disease ◽

Scid Mice ◽

White Pulp ◽

Activation Markers ◽

Host Disease ◽

Graft Versus Host ◽

Human T Cell

Abstract Surprisingly little graft-versus-host disease (GVHD) has been observed in severe combined immunodeficient (SCID) mice injected intraperitoneally (IP) with human blood lymphocytes (hu-PBL-SCID), which raised the question as to whether GVHD in such a distant species is sporadic or suppressed because of immunologic reasons. After screening for blood T-cell chimerism, we hereby describe generalized lethal xenogeneic human GVHD in unconditioned SCID chimeras, which resembles GVHD in SCID mice injected with allogeneic lymphocytes. We adapted an immunocytochemical slide method for minute cell numbers, which allowed us to follow, by multimarker phenotyping of weekly mouse- tail bleeds, the chimeric status of 100 hu-PBL-SCID injected with 10(7) or 10(8) hu-PBL of Epstein-Barr virus- (EBV-) donors. More than half of the mice showed no or less than 2% T cells. However, 13% to 21% developed substantial blood T-lymphocyte chimerism (10% to 80% human CD+ cells) and high mortality. Immunohistology showed more human CD8+ than CD4+ T cells in the splenic white pulp. The cells developed HLA-DR activation markers and infiltrated the red pulp where human B cells also appeared. Expression of activation and proliferation markers increased within 5 to 6 weeks. Many human CD3+ cells were also found in the portal triads of the liver and in the lung, pancreas, and kidney. The thymus also became heavily infiltrated. The intestines and skin of hu-PBL-SCID were less infiltrated by donor cells than in SCID with allogeneic GVHD. The tongue contained almost no human T cells. Our data show that a relatively low overall incidence of human xenogeneic GVHD, even when high numbers of human PBL are injected, is the consequence of a dichotomy between mice with no or transient T-cell chimerism and a minority of mice with high-blood T-lymphocyte chimerism and GVHD mortality.

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Interleukin-2 inhibits graft-versus-host disease-promoting activity of CD4+ cells while preserving CD4- and CD8-mediated graft-versus-leukemia effects

Blood ◽

10.1182/blood.v83.9.2560.2560 ◽

1994 ◽

Vol 83 (9) ◽

pp. 2560-2569 ◽

Cited By ~ 67

Author(s):

M Sykes ◽

MW Harty ◽

GL Szot ◽

DA Pearson

Keyword(s):

T Cells ◽

T Cell ◽

Graft Versus Host Disease ◽

Interleukin 2 ◽

Cell Subset ◽

Spleen Cells ◽

Host Disease ◽

Graft Versus Host ◽

T Cell Subset ◽

Graft Versus Leukemia

Abstract We have recently shown that a short course of high-dose interleukin-2 (IL-2) can markedly inhibit the graft-versus-host disease (GVHD)- promoting activity of donor CD4+ T cells. The difficulty in dissociating GVHD-promoting from graft-versus-leukemia (GVL) effects of alloreactive donor T cells currently prevents clinical bone marrow transplantation (BMT) from fulfilling its full potential. To test the capacity of IL-2 treatment to promote such a dissociation, we have developed a new murine transplantable acute myelogenous leukemia model using a class II major histocompatibility complex-positive BALB/c Moloney murine leukemia virus-induced promonocytic leukemia, 2B-4–2. BALB/c mice receiving 2.5 x 10(5) 2B-4–2 cells intravenously 1 week before irradiation and syngeneic BMT died from leukemia within 2 to 4 weeks after BMT. Administration of syngeneic spleen cells and/or a 2.5- day course of IL-2 treatment alone did not inhibit leukemic mortality. In contrast, administration of non-T-cell-depleted fully allogeneic B10 (H-2b) spleen cells and T-cell-depleted B10 marrow led to a significant delay in leukemic mortality in IL-2-treated mice. In these animals GVHD was inhibited by IL-2 treatment. GVL effects were mediated entirely by donor CD4+ and CD8+ T cells. Remarkably, IL-2 administration did not diminish the magnitude of the GVL effect of either T-cell subset. This was surprising, because CD4-mediated GVHD was inhibited in the same animals in which CD4-mediated GVL effects were not reduced by IL-2 treatment. These results suggest a novel mechanism by which GVHD and GVL effects of a single unprimed alloreactive T-cell subset can be dissociated; different CD4 activities promote GVHD and GVL effects, and the former, but not the latter activities are inhibited by treatment with IL-2.

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Homeostatic expansion and repertoire regeneration of donor T cells during graft versus host disease is constrained by the host environment

Blood ◽

10.1182/blood-2006-12-061713 ◽

2007 ◽

Vol 109 (12) ◽

pp. 5502-5510 ◽

Cited By ~ 13

Author(s):

Jack Gorski ◽

Xiao Chen ◽

Mariya Gendelman ◽

Maryam Yassai ◽

Ashley Krueger ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Graft Versus Host Disease ◽

Cell Expansion ◽

Host Disease ◽

Host Environment ◽

Graft Versus Host ◽

T Cell Reconstitution ◽

T Cell Expansion ◽

Cell Defect

Abstract Graft versus host disease (GVHD) typically results in impaired T-cell reconstitution characterized by lymphopenia and repertoire skewing. One of the major causes of inadequate T-cell reconstitution is that T-cell survival and expansion in the periphery are impaired. In this report, we have performed adoptive transfer studies to determine whether the quantitative reduction in T-cell numbers is due to an intrinsic T-cell defect or whether the environmental milieu deleteriously affects T-cell expansion. These studies demonstrate that T cells obtained from animals with graft-versus-host disease (GVHD) are capable of significant expansion and renormalization of an inverted CD4/CD8 ratio when they are removed from this environment. Moreover, these cells can generate complex T-cell repertoires early after transplantation and are functionally competent to respond to third-party alloantigens. Our data indicate that T cells from mice undergoing GVHD can respond to homeostatic signals in the periphery and are not intrinsically compromised once they are removed from the GVHD environment. We thereby conclude that the host environment and not an intrinsic T-cell defect is primarily responsible for the lack of effective T-cell expansion and diversification of complex T-cell repertoires that occurs during GVHD.

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