The yin and yang of adaptive immunity in allogeneic hematopoietic cell transplantation: donor antigen-presenting cells can either augment or inhibit donor T cell alloreactivity.
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Animals↗
Biomedical subjects
Edmund K Waller
Publications and source records attributed to Edmund K Waller.
Treatment of relapsed acute leukemia after allogeneic transplantation: a single center experience.
Relapsed acute leukemia after allogeneic transplantation has a poor prognosis and most reports have focused on the role of second transplantations in relapsed patients. We report our single-institution experience on the management of relapsed acute leukemia after allogeneic transplantation. We aimed to describe the outcome of relapsed acute leukemia after allogeneic transplantation at our institution and investigate whether maneuvers intended to augment donor T cell allogeneic reactivity were associated with durable graft-versus-leukemia effects. We analyzed 310 patients with acute leukemia who received allogeneic hematopoietic progenitor cell transplants from HLA-matched donors between 1982 and 2005 (229 with acute myelogenous leukemia, 81 with acute lymphoblastic leukemia). Mean post-transplant follow-up was 5 years (range, 0.5-22 years). Factors associated with relapse incidence, therapy for relapse, response to treatment, and post-relapse survival were assessed. One hundred of 310 patients (32%) with acute leukemia relapsed after transplantation, including 28 of 81 patients (35%) with acute lymphoblastic leukemia and 72 of 229 (31%) with acute myelogenous leukemia at a median of 136 days after transplantation. Median post-relapse survival periods were 51 days for the 69 patients who received chemotherapy/supportive care, 84 days for 11 recipients of donor lymphocyte infusions, 303 days for 13 recipients of second transplants, and 442 days for 7 patients treated with interferon-alpha and granulocyte-macrophage colony-stimulating factor. A multivariable Cox regression analysis indicated that a longer time to relapse after transplantation, peripheral blood as source of stem cells, and initial post-relapse therapy with cytokines, donor lymphocyte infusions, or second transplants were associated with improved post-relapse survival (P <.001, <.001, and .025). The outlook for patients with post-transplant relapse of acute leukemia is extremely poor; currently, no single therapy consistently results in durable remissions. Our study highlights the need for clinical trials in this area. Therapy with granulocyte-macrophage colony stimulating factor and interferon-alpha-2b is promising and will be pursued in a prospective trial at our center.
Adolescent↗
Expression of the plasmacytoid dendritic cell marker BDCA-2 supports a spectrum of maturation among CD4+ CD56+ hematodermic neoplasms.
CD4+CD56+ hematodermic neoplasms are rare, aggressive hematopoietic malignancies usually presenting with cutaneous masses followed by a leukemic phase. The blastic morphology, CD56 expression and lack of definitive myeloid or T-cell markers initially resulted in assignment of this tumor to the NK-cell lineage. Accumulating evidence now suggests that these neoplasms represent malignant counterparts to the plasmacytoid dendritic cell. BDCA-2 is a cell surface protein whose expression is restricted to human plasmacytoid dendritic cells, in a differentiation stage-specific manner. In the current study, we assessed expression of BDCA-2 in CD4+CD56+ hematodermic neoplasms using a new antibody reagent we developed for use in fixed tissue sections. In 10 of 19 cases of CD4+CD56+ hematodermic neoplasm, BDCA-2 immunoreactivity was detected, whereas no expression was observed in NK-lineage tumors (0 of six). Interestingly, expression of terminal deoxynucleotidyl transferase, a marker of immaturity/blast stage, was significantly and negatively correlated with BDCA-2 in CD4+CD56+ hematodermic neoplasms whereas a positive correlation was observed between BDCA-2 and CD7. These findings demonstrate that BDCA-2 is expressed predominantly in the CD7+ subset of hematodermic neoplasms, and similar to non-neoplastic plasmacytoid dendritic cells, expression indicates a relatively more mature differentiation state. Clinical follow-up data confirm the aggressiveness of these tumors and suggests that BDCA-2 immunoreactivity, as identified here, may herald a significant reduction in survival.
Antigens, Neoplasm↗
Maintenance therapy with thalidomide improves overall survival after autologous hematopoietic progenitor cell transplantation for multiple myeloma.
BACKGROUND: High-dose chemotherapy with autologous hematopoietic progenitor cell (HPC) transplantation improves survival for patients with multiple myeloma (MM); however, most patients develop recurrent disease after undergoing transplantation, and new treatment approaches are needed. The objective of this retrospective review of autologous HPC transplantation for patients with MM was to evaluate the impact of conditioning regimens and posttransplantation therapy on survival. METHODS: The authors reviewed 112 patients with MM who received autologous HPC grafts at their institution. Between June 1992 and August 2001, 54 patients received busulfan, cyclophosphamide, and etoposide (Bu/Cy/VP-16), and 58 patients received high-dose melphalan (MEL-200) followed by autologous HPC transplantation. After transplantation, 36 patients received thalidomide for maintenance or salvage therapy, and 76 patients received no posttransplantation thalidomide. RESULTS: At a median follow-up of 58 months, the median survival was 54 months. There was no statistically significant difference noted with regard to response to conditioning regimen, progression-free survival, or overall survival between the Bu/Cy/VP-16 and MEL-200 cohorts. Patients who received thalidomide after transplantation had improved median survival (65.5 months) compared with patients who did not receive thalidomide (44.5 months; P = .09). When they were separated according to reasons for thalidomide use, patients who received thalidomide as maintenance had improved overall survival compared with patients who received thalidomide as salvage (65 months vs. 54 months; P = .05). CONCLUSIONS: Combination chemotherapy provided no advantage over high-dose melphalan in patients with MM who underwent autologous HPC transplantation. The posttransplantation use of thalidomide seemed to improve the survival of patients compared with historical controls from the prethalidomide era. Further prospective trials are underway to confirm the benefit of thalidomide in the posttransplantation setting.
Adult↗
Apoptotic donor leukocytes limit mixed-chimerism induced by CD40-CD154 blockade in allogeneic bone marrow transplantation.
"Mini" allogeneic bone marrow transplants using non-myeloablative conditioning have reduced early treatment-related mortalities, but graft-versus-host disease (GVHD) and graft rejection remain clinical problems. Our preliminary studies indicated that low-dose busulfan conditioning and costimulatory blockade using anti-CD154 monoclonal antibody (mAb) in combination with a pretransplantation "tolerating" dose of bone marrow (BM) cells were sufficient to establish stable mixed-chimerism without GVHD when transplanting moderate doses of T cell depleted (TCD)-BM from major histocompatibility complex (MHC) fully-mismatched donors (Adams AB, Durham MM, Kean L, et al. J Immunol. 2001;167:1103-1111). In this study, donor splenocytes were administered before transplantation as a tolerating cell infusion with a conditioning regimen consisting of low-dose busulfan and anti-CD154 mAb. We compared the ability of viable and apoptotic donor cells of different ex vivo treatments and purified different donor cell populations (CD3(+), CD3(-), CD11b(+), and CD11b(-) splenocytes) to induce tolerance and enhance donor chimerism in a MHC mismatched model of murine bone marrow transplantation. We found that mixed chimerism without GVHD was enhanced by pretransplantation administration of viable allogeneic splenocytes and diminished in mice with prior exposure to apoptotic/necrotic donor splenocytes. CD11b(+)-enriched splenocytes more potently enhanced donor chimerism compared to unfractionated splenocytes or other splenocyte subsets. Mixed lymphocyte cultures demonstrated that apoptotic stimulators overcame the immune-tolerating activity of anti-CD154 mAb and led to increased interferon gamma and tumor necrosis factor alpha synthesis, increased proliferation of responder T cells, and decreased production of interleukin-10. In conclusion, viable donor splenocytes administered before transplantation in combination with costimulatory blockade induced tolerance and enhanced donor chimerism, whereas pretransplantation administration of apoptotic/necrotic donor cells led to host T cell activation and decreased overall donor engraftment.
Animals↗
Graft engineering using ex vivo methods to limit GVHD: fludarabine treatment generates superior GVL effects in allogeneic BMT.
OBJECTIVE: To compare the abilities of different ex vivo methods of treating donor lymphocytes to inhibit graft-vs-host disease (GVHD) while preserving graft-vs-leukemia (GVL) activity in murine models of allogeneic bone marrow transplantation. METHODS: Donor/recipient pairs included MHC fully mismatched, MHC haplomismatched, and MiHA mismatched strain combinations. T cell-depleted BM (TCD-BM) was transplanted in combination with untreated, fludarabine-treated, 7.5-Gy gamma-irradiated, or psoralen/UVA (PUVA)-treated splenocytes. GVL activity was studied by adding a lethal number of recipient-type lymphoma cells. Posttransplant survival was determined, and GVHD and GVL activity were assessed by clinical and pathological scoring. Hematopoietic chimerism and donor T-cell expansion were analyzed by flow cytometry of peripheral blood samples at 30 and 60 days posttransplant. RESULTS: Allogeneic splenocytes treated with fludarabine, 7.5 Gy gamma-irradiation, or PUVA had significantly diminished GVHD activity, and all treated donor T cells facilitated engraftment by low-dose TCD-BM. Allogeneic splenocytes treated with fludarabine and, to a lesser extent, PUVA retained GVL activity and contributed more to donor T-cell chimerism compared to gamma-irradiated donor splenocytes. CONCLUSION: Among ex vivo methods of treating donor T cells to limit their proliferative capacity, fludarabine exposure had the greatest differential ability to inhibit the GVHD activity of allogeneic lymphocytes, while preserving their GVL activity and ability to engraft recipients. Thus, ex vivo treatment with fludarabine was superior to gamma-irradiation or PUVA in separating GVL from GVHD activity in murine models of allogeneic bone marrow transplantation.
Animals↗
Results of a clinical phase I dose-escalation study of cytarabine in combination with fixed-dose vinorelbine, paclitaxel, etoposide and cisplatin for the treatment of relapsed/refractory lymphoma.
Management of relapsed lymphoma depends upon the variables of chemosensitive disease and successful stem cell mobilization. The microtubule specific agents, paclitaxel and vinorelbine, have efficacy in relapsed lymphoma and can enhance stem cell mobilization. We performed a phase I dose-escalation study of cytarabine combined with fixed doses of vinorelbine, paclitaxel, etoposide and cisplatin (VTEPA) for patients with relapsed/refractory lymphoma. The regimen consisted of paclitaxel 175 mg/m2 and vinorelbine 30 mg/m2 on day 1; cisplatin 20 mg/m2 and etoposide 100 mg/m2 over 4 h on days 2 - 5. Cytarabine 2 g m/m2 over 4 h, in successive cohorts on 1, 2, or 3 consecutive days: cohort A day 5; cohort B days 4 - 5; and cohort C days 3 - 5. Sixteen patients (Hodgkin's disease, n = 6; non-Hodgkin's lymphoma, n = 10) were enrolled. Fourteen of 16 patients (88%) had refractory and seven patients (44%) had primary refractory disease. Major toxicities included hematologic toxicity, mucositis and infectious complications. Infectious complications (10/16 patients) included neutropenic fever, sepsis and fungal pneumonia. Dose-limiting toxicity was achieved in cohort C, which received three doses of cytarabine. There were 33% partial responses, 27% stable disease and 40% progressive disease following a single cycle of VTEPA. Two of 16 patients suffered treatment-related mortality. Five patients went on to receive autologous (n = 4) or allogeneic transplant (n = 1), and five out of seven patients in this heavily pretreated group who received VTEPA for mobilization of an autologous graft were successfully collected. The recommended dose of cytarabine for further evaluation in a phase II study is 2 g m/m2 for 2 consecutive days in combination with VTEPA. Treatment of subjects with relapsed/refractory lymphoma using VTEPA as second- or third-line salvage therapy produced remissions in some patients and permitted collection of grafts and subsequent autologous transplantation, supporting a planned phase II trial.
Adult↗
The combination of the farnesyl transferase inhibitor lonafarnib and the proteasome inhibitor bortezomib induces synergistic apoptosis in human myeloma cells that is associated with down-regulation of p-AKT.
The identification of signaling pathways critical to myeloma growth and progression has yielded an array of novel agents with clinical activity. Multiple myeloma (MM) growth is IL-6 dependent, and IL-6 is secreted in an autocrine/paracrine fashion with signaling via the Ras/Raf/mitogen-activated protein kinase (MAPK) pathway. We hypothesized that combining a Ras pathway inhibitor (lonafarnib, SCH66336) with a proteasome inhibitor (bortezomib, Velcade, PS-341) would enhance myeloma-cell killing. MM cell lines and primary human cells were used to test either single agent bortezomib, lonafarnib, or the combination on MM signaling and apoptosis. Combination therapy induced synergistic tumor-cell death in MM cell lines and primary MM plasma cells. Cell death was rapid and associated with increased caspase 3, 8, and 9 cleavage and concomitant down-regulation of p-AKT. Down-regulation of p-AKT was seen only in combination therapy and not seen with either single agent. Cells transfected with constitutively active p-AKT, wild-type AKT, or Bcl-2 continued to demonstrate synergistic cell death in response to the combination. The order of addition was critically important, supporting bortezomib followed by lonafarnib as the optimal schedule. The combination of a proteasome inhibitor and farnesyl transferase inhibitor demonstrates synergistic myeloma-cell death and warrants further preclinical and clinical studies.
Apoptosis↗
Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma.
Bortezomib, a proteasome inhibitor with efficacy in multiple myeloma, is associated with thrombocytopenia, the cause and kinetics of which are different from those of standard cytotoxic agents. We assessed the frequency, kinetics, and mechanism of thrombocytopenia following treatment with bortezomib 1.3 mg/m2 in 228 patients with relapsed and/or refractory myeloma in 2 phase 2 trials. The mean platelet count decreased by approximately 60% during treatment but recovered rapidly between treatments in a cyclic fashion. Among responders, the pretreatment platelet count increased significantly during subsequent cycles of therapy. The mean percent reduction in platelets was independent of baseline platelet count, M-protein concentration, and marrow plasmacytosis. Plasma thrombopoietin levels inversely correlated with platelet count. Murine studies demonstrated a reduction in peripheral platelet count following a single bortezomib dose without negative effects on megakaryocytic cellularity, ploidy, or morphology. These data suggest that bortezomib-induced thrombocytopenia is due to a reversible effect on megakaryocytic function rather than a direct cytotoxic effect on megakaryocytes or their progenitors. The exact mechanism underlying bortezomib-induced thrombocytopenia remains unknown but it is unlikely to be related to marrow injury or decreased thrombopoietin production.
Adult↗
Peripheral blood mononuclear cells acquire myofibroblast characteristics in granulation tissue.
BACKGROUND: Bone marrow-derived cell populations possess progenitor cell capacities. Emerging evidence also suggests significant plasticity of differentiated mononuclear cell lineages. We therefore assessed the distribution of transplanted peripheral blood mononuclear cells (PBMCs) in granulation tissue formation, and evaluated their possible transdifferentiation into myofibroblasts. METHODS: Silastic tubes were inserted into the peritoneal cavity of rats, followed by injection of PKH26-labelled PBMCs isolated from donor animals. At 3, 14 and 21 days, the distribution of PKH26(+) cells as well as their colocalization with myofibroblast/smooth muscle cell [alpha-smooth muscle (alpha-SM) actin] or macrophage markers (ED1/ED2) were determined. RESULTS: Round-shaped PKH26(+) cells accumulated around the implants at 3 days, while myofibroblasts were rare. Later, peritoneal granulation tissue constituted an inner, multilayered capsule primarily comprising alpha-SM actin(+) cells that was surrounded by more loosely organized inflammatory connective tissue. PKH26-labelled, spindle-shaped cells were abundantly found in tissue capsules. As a key finding, granulation tissue at 14 and 21 days contained cells with both PKH26 and alpha-SM actin labelling. Accordingly, a subpopulation of cells staining positive for macrophage markers showed a spindle-shaped morphology and alpha-SM actin expression. CONCLUSIONS: Transplanted PBMCs contribute to granulation tissue, and acquire myofibroblast characteristics during de novo tissue formation. Mononuclear cells may transdifferentiate into myofibroblast-like cells within an inflammatory environment.
Actins↗
Amotosalen-treated donor T cells have polyclonal antigen-specific long-term function without graft-versus-host disease after allogeneic bone marrow transplantation.
We have previously shown that amotosalen HCl (S-59 psoralen)-treated donor splenocytes, which have limited proliferative capacity in vitro, can protect major histocompatibility complex-mismatched bone marrow transplant (BMT) recipients from lethal murine cytomegalovirus infection without causing graft-versus-host disease. In this study, we further investigated the effects of amotosalen-treated donor T cells on immune reconstitution after allogeneic BMT. We were surprised to find that amotosalen-treated donor T cells persisted long-term in vivo, comprising 6% to 10% on average of the T-cell compartment of transplant recipients at 4 months after transplantation. Donor T cells derived from amotosalen-treated splenocytes were predominantly polyclonal CD44 hi/int CD8 + memory T cells and were functionally active, synthesizing interferon gamma in response to stimulation with murine cytomegalovirus antigen. Amotosalen-treated donor T cells, reisolated from BMT recipients' spleens >/=4 months after transplantation, proliferated in vitro, thus indicating repair of amotosalen-mediated DNA cross-links. Compared with infusion of untreated donor splenocytes, amotosalen-treated cells enhanced thymopoiesis by bone marrow-derived stem cells in BMT recipients. However, amotosalen treatment abrogated the thymopoietic activity of lymphoid progenitor cells among the donor splenocytes. Thus, infusion of amotosalen-treated donor T cells produced rapid immune reconstitution after major histocompatibility complex-mismatched BMT by transferring long-lived polyclonal memory T cells with antiviral activity and also by enhancing bone marrow-derived thymopoiesis. This is a novel approach to adoptive immunotherapy in allogeneic BMT.
Animals↗
Vaccinia virus tropism for primary hematolymphoid cells is determined by restricted expression of a unique virus receptor.
The presumed broad tropism of poxviruses has stymied attempts to identify both the cellular receptor(s) and the viral determinant(s) for binding. Detailed studies of poxvirus binding to and infection of primary human cells have not been conducted. In particular, the determinants of target cell infection and the consequences of infection for cells involved in the generation of antiviral immune responses are incompletely understood. In this report, we show that vaccinia virus (VV) exhibits a more restricted tropism for primary hematolymphoid human cells than has been previously recognized. We demonstrate that vaccinia virus preferentially infects antigen-presenting cells (dendritic cells, monocytes/macrophages, and B cells) and activated T cells, but not resting T cells. The infection of activated T cells is permissive, with active viral replication and production of infectious progeny. Susceptibility to infection is determined by restricted expression of a cellular receptor that is induced de novo upon T-cell activation and can be removed from the cell surface by either trypsin or pronase treatment. The VV receptor expressed on activated T cells displays unique characteristics that distinguish it from the receptor used to infect cell lines in culture. The observed restricted tropism of VV may have significant consequences for the understanding of natural poxvirus infection and immunity and for poxvirus-based vaccine development.
Animals↗
Donor antigen-presenting cells regulate T-cell expansion and antitumor activity after allogeneic bone marrow transplantation.
Delayed immunologic recovery after allogeneic bone marrow transplantation (BMT) represents a major cause of morbidity and mortality that limits the overall success of the transplantation procedure. Recent clinical data suggest that a subset of donor dendritic cells may inhibit the graft-versus-tumor activity of donor T cells. We studied the immunoregulatory activity of donor dendritic cells in allogeneic BMT between major histocompatibility complex-disparate strains of mice. Bone marrow grafts enriched or depleted of CD11b- and CD11b+ dendritic cell subsets by immunomagnetic cell sorting were combined with small numbers of congenic splenic T cells. Recipients of CD11b-depleted bone marrow had significant posttransplantation expansion of donor spleen-derived CD4+ memory T cells compared with recipients of unmanipulated bone marrow. CD11b depletion enhanced the antitumor activity of the splenic donor T cells without producing significant graft-versus-host disease and resulted in long-term survival after a supralethal dose of T-cell leukemia administered after BMT. Expansion of donor spleen-derived T cells was proportional to the number of CD11b- dendritic cells in the bone marrow graft and was associated with increased levels of serum interferon-gamma. Thus, manipulating the content of donor antigen-presenting cells in allogeneic BMT is a novel strategy to activate donor memory T cells and enhance allogeneic graft-versus-leukemia effects with minimal graft-versus-host disease.
Animals↗
A randomized trial comparing the combination of granulocyte-macrophage colony-stimulating factor plus granulocyte colony-stimulating factor versus granulocyte colony-stimulating factor for mobilization of dendritic cell subsets in hematopoietic progenitor cell products.
The ability of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) administration to increase the content of blood leucocytes and hematopoietic progenitor cells (HPCs) is well established, yet the effect of these cytokines on immune function is less well described. Recent data indicate that plasmacytoid dendritic cells (DC2) may inhibit cellular immune response. We hypothesized that administration of the combination of G-CSF and GM-CSF after chemotherapy would reduce the type 2, or plasmacytoid, DC2 content of the autologous blood HPC grafts compared with treatment with G-CSF alone. To test this hypothesis, 35 patients with lymphoma and myeloma were randomized to receive either G-CSF or the combination of G-CSF plus GM-CSF after chemotherapy, and blood HPC grafts were collected by apheresis. Cytokine-related adverse events between the 2 groups were similar. More than 2 x 10(6)CD34 + cells per kilogram were collected by apheresis in 14 of 18 subjects treated with G-CSF and in 16 of 17 subjects treated with GM-CSF plus G-CSF ( p = not significant). There were minor differences between the 2 groups with respect to the content of T cells and CD34 + cells in the apheresis products. However, grafts collected from recipients of the combination of GM-CSF plus G-CSF had significantly fewer DC2 cells and similar numbers of DC1 cells compared with recipients treated with G-CSF alone. A third cohort of patients received chemotherapy followed by the sequential administration of G-CSF and the addition of GM-CSF 6 days later. Grafts from these patients had a markedly reduced DC2 content compared with those from patients treated either with G-CSF alone or with the concomitant administration of both cytokines. These data, and recent data that cross-presentation of antigen by DC2 cells may induce antigen-specific tolerance among T cells, suggest that GM-CSF during mobilization of blood HPC grafts may be a clinically applicable strategy to enhance innate and acquired immunity after autologous and allogeneic HPC transplantation.
Adult↗
Cellular immunotherapy and cancer.
Recent data indicate that cellular immune responses can produce an anticancer effect. Two types of cellular immune responses appear to be clinically relevant: antigen specific immunity mediated by T cells that recognize tumor-associated peptide antigen expressed on surface HLA class I or class II molecules, and antigen nonspecific immune responses mediated by natural killer (NK) cells that are activated by the failure to recognize cognate "self" HLA class I molecules. The graft-versus-tumor effect of allogeneic transplants using HLA-matched donors is mediated by antigen-specific T cells, while allogeneic transplantation using HLA mismatched donors can also lead to donor NK cells with potent antitumor activity. HLA mismatched haplo-identical transplants can exert a powerful antileukemia effect based on expansion of antigen nonspecific donor NK cells, but slow recovery of donor T cells is associated with a profound immune deficiency and increased opportunistic infections that limit the overall clinical success of this type of transplant maneuver. The focus for most immunologic maneuvers designed to enhance the graft-versus-tumor effect has been on strategies to expand or enhance the activity of antigen-specific donor T cells that recognize host tumor cells. In the case of hematologic malignancies, the activity of donor T cells against tumor cells is regulated by dendritic cells, which can augment or inhibit cellular immune responses. Future successes in enhancing the patients' own cellular immune responses to cancer will likely be based on activation of T cells by the appropriate dendritic cell subset and, in the case of tumors that have down-regulated HLA class I expression, by activated NK cells.
Humans↗
Reconstructing immunity after allogeneic transplantation.
A major goal of our research is to reduce the graft-vs-host disease (GVHD) activity of allogeneic donor T cells in bone marrow transplantation (BMT), while preserving graft-vs-tumor (GVT) effects. Using ex vivo immunosuppressive strategies and cell-separation techniques to modulate the graft prior to transplantation, we examined the roles of different donor immune cells on GVHD and GVT effects in allogeneic mouse models. Our results demonstrate that donor-memory CD4 T cells facilitate posttransplant immunological reconstitution without causing GVHD, whereas transplantation of equal numbers of donor naïve CD4 T cells leads to fatal GVHD. The initial events of donor T cells interacting with antigen-presenting cells (APCs) in the transplant recipient appear to be critical to the development of GVT, GVHD, or anergy to alloantigens. In the setting of clinical BMT, increased numbers of donor type 2 dendritic cells (DCs) were associated with an increased rate of posttransplant relapse, and decreased rates of chronic GVHD. In a mouse transplant model, manipulation of the DC content of bone marrow grafts was achieved by depletion of CD11b+ cells. Mice transplanted with CD11b- depleted marrow showed enhanced posttransplant expansion of memory T cells with markedly improved GVT activity and limited GVHD compared to recipients of unmanipulated marrow. A model that differentiates GVT from GVHD based on interaction of T-cell subsets with DC subsets is proposed.
Animals↗
Granulocyte-macrophage-colony-stimulating factor and other cytokines: as adjuncts to cancer immunotherapy, stem cell transplantation, and vaccines.
A new role for myeloid-acting cytokines in regulating immune responses has been proposed based upon their activity on dendritic cell (DC) maturation and activation. Subsets of DCs may augment or inhibit cellular immune responses. Enhanced DC1 activity has been associated with enhanced cytotoxic immune responses. Granulocyte-macrophage-colony-stimulating factor (GM-CSF) and granulocyte-colony- stimulating factor (G-CSF) differ by their effects on enhancing the numbers or activity of DC1 or DC2 subsets of DCs, respectively. The increase in DC1 content and activity following local and systemic GM-CSF administration support a role for GM-CSF as an immune stimulant and vaccine adjuvant in cancer patients. The clinical activity of GM-CSF in anti-tumor immune responses has been documented in its use in tumor cell and DC vaccines, but a significant anti-tumor effect of parenterally administered GM-CSF in a randomized clinical study has yet to be consistently demonstrated. The successful use of myeloid acting cytokines to enhance anti-tumor responses will likely require targeting these drugs or activating DCs directly into the tumor microenvironment.
Cancer Vaccines↗
Allogeneic T cells treated with amotosalen prevent lethal cytomegalovirus disease without producing graft-versus-host disease following bone marrow transplantation.
Infusion of donor antiviral T cells can provide protective immunity for recipients of hemopoietic progenitor cell transplants, but may cause graft-vs-host disease (GVHD). Current methods of separating antiviral T cells from the alloreactive T cells that produce GVHD are neither routine nor rapid. In a model of lethal murine CMV (MCMV) infection following MHC-mismatched bone marrow transplantation, infusion of MCMV-immune donor lymphocytes pretreated with the DNA cross-linking compound amotosalen prevented MCMV lethality without producing GVHD. Although 95% of mice receiving 30 x 10(6) pretreated donor lymphocytes survived beyond day +100 without MCMV disease or GVHD, all mice receiving equivalent numbers of untreated lymphocytes rapidly died of GVHD. In vitro, amotosalen blocked T cell proliferation without suppressing MCMV peptide-induced IFN-gamma production by MCMV-primed CD8(+) T cells. In vivo, pretreated lymphocytes reduced hepatic MCMV load by 4-log(10) and promoted full hemopoietic chimerism. Amotosalen-treated, MCMV tetramer-positive memory (CD44(high)) CD8(+) T cells persisted to day +100 following infusion, and expressed IFN-gamma when presented with viral peptide. Pretreated T cells were effective at preventing MCMV lethality over a wide range of concentrations. Thus, amotosalen treatment rapidly eliminates the GVHD activity of polyclonal T cells, while preserving long-term antiviral and graft facilitation effects, and may be clinically useful for routine adoptive immunotherapy.
Animals↗