Reduction of myeloid-derived suppressor cells reinforces the anti-solid tumor effect of recipient leukocyte infusion in murine neuroblastoma-bearing allogeneic bone marrow chimeras.

Allogeneic hematopoietic stem cell transplantation is an emerging treatment option for solid tumors because of its capacity to elicit immune graft-versus-tumor effects. However, these are often limited and associated with GvHD. Adoptive recipient leukocyte infusion (RLI) was shown to enhance anti-tumor responses of allogeneic bone marrow transplantation in murine neuroblastoma (Neuro2A)-bearing chimeras. In contrast to the clinically used donor leukocyte infusion, the RLI anti-tumor effect-elicited by host-versus-graft lymphohematopoietic reactivity-does not cause GvHD; however, the tumor growth-inhibitory effect is incomplete, because overall survival is not prolonged. Here, we studied the anti-solid tumor mechanisms of RLI with the objective to improve its efficacy. Host-versus-graft reactivity following RLI was associated with a systemic cytokine storm, lymph node DC activation, and systemic expansion of host-derived IFN-γ-expressing CD4+ T cells and IFN-γ-and granzyme B-expressing CD8+ T cells, which acquired killing activity against Neuro2A and third-party tumor cells. The tumor showed up-regulation of MHC class I and a transient accumulation of IFN-γ-and granzyme B-expressing CD8+ T cells: the intra-tumor decline in cytotoxic CD8+ T cells coincided with a systemic-and to a lesser extent intra-tumoral-expansion of MDSC. In vivo MDSC depletion with 5-FU significantly improved the local tumor growth-inhibitory effect of RLI as well as overall survival. In conclusion, the RLI-induced alloreactivity gives rise to a host-derived cytotoxic T-cell anti-neuroblastoma response, but also drives an expansion of host-type MDSC that counteracts the anti-tumor effect. This finding identifies MDSC as a novel target to increase the effectiveness of RLI, and possibly other cancer immunotherapies.

The graft-versus-neuroblastoma effect of allogeneic hematopoietic stem cell transplantation, a review of clinical and experimental evidence and a perspective on mechanisms.

Despite aggressive treatment, patients with high-risk neuroblastoma face high relapse rates and bleak prognoses. Increasing evidence that neuroblastoma cells are or can become immunogenic has stimulated research into novel therapies based on triggering or enhancing tumor immunity. Here we review clinical and experimental studies on this subject, the underlying immune mechanisms and perspectives for clinical application. Allogeneic hematopoietic stem cell transplantation has proven to be of substantial benefit in the treatment of certain leukemias through the generation of a graft-versus-leukemia-effect and has become of interest as a possible treatment for patients with solid tumors, including neuroblastoma.

Recipient leukocyte infusion enhances the local and systemic graft-versus-neuroblastoma effect of allogeneic bone marrow transplantation in mice.

Allogeneic hematopoietic stem cell transplantation and donor leukocyte infusion (DLI) may hold potential as a novel form of immunotherapy for high-risk neuroblastoma. DLI, however, carries the risk of graft-versus-host disease (GvHD). Recipient leukocyte infusion (RLI) induces graft-versus-leukemia responses without GvHD in mice and is currently being explored clinically. Here, we demonstrate that both DLI and RLI, when given to mixed C57BL/6→A/J radiation chimeras carrying subcutaneous Neuro2A neuroblastoma implants, can slow the local growth of such tumors. DLI provoked full donor chimerism and GvHD; RLI produced graft rejection but left mice healthy. Flow cytometric studies showed that the chimerism of intratumoral leukocytes paralleled the systemic chimerism. This was associated with increased CD8/CD4 ratios, CD8+ T-cell IFN-γ expression and NK-cell Granzyme B expression within the tumor, following both DLI and RLI. The clinically safe anti-tumor effect of RLI was further enhanced by adoptively transferred naïve recipient-type NK cells. In models of intravenous Neuro2A tumor challenge, allogeneic chimeras showed superior overall survival over syngeneic chimeras. Bioluminescence imaging in allogeneic chimeras challenged with luciferase-transduced Neuro2A cells showed both DLI and RLI to prolong metastasis-free survival. This is the first experimental evidence that RLI can safely produce a local and systemic anti-tumor effect against a solid tumor. Our data indicate that RLI may provide combined T-cell and NK-cell reactivity effectively targeting Neuro2A neuroblastoma.

IL-7 is required for the development of the intrinsic function of marginal zone B cells and the marginal zone microenvironment.

The characteristic microarchitecture of the marginal zone (MZ), formed by locally interacting MZ-specific B cells, macrophages, and endothelial cells, is critical for productive marginal zone B cell (MZB cell) Ab responses. Reportedly, IL-7-deficient mice, although severely lymphopenic, retain small numbers of CD21(high)CD23(low) B cells consistent with MZB cell phenotype, suggesting that IL-7 signaling is not exclusively required for MZB cell lymphopoiesis. In this study, we investigated the function of IL-7(-/-) MZB cells and the IL-7(-/-) microenvironment using a model of hamster heart xenograft rejection, which depends exclusively on MZB cell-mediated production of T cell-independent IgM xenoantibodies (IgMXAb). C57BL/6-IL-7(-/-) mice accepted xenografts indefinitely and failed to produce IgMXAb, even after transfer of additional IL-7(-/-) or wild-type C57BL/6 MZB cells. Transfer of wild-type but not IL-7(-/-) B cells enabled SCID mice to produce IgMXAb. When transferred to SCID mice, wild-type but not IL-7(-/-) B cells formed B cell follicles with clearly defined IgM(+), MOMA-1(+), and MAdCAM-1(+) MZ structures. Conversely, adoptively transferred GFP(+) C57BL/6 B cells homed to the MZ area in a SCID but not an IL-7(-/-) environment. Naive IL-7(-/-) mice showed absent or aberrant splenic B cell structures. We provide evidence that IL-7 is critical for the development of the intrinsic function of MZB cells in producing rapidly induced IgM against T cell-independent type II Ags, for their homing potential, and for the development of a functional MZ microanatomy capable of attracting and lodging MZB cells.

G-CSF stem cell mobilization in human donors induces polymorphonuclear and mononuclear myeloid-derived suppressor cells.

The role of myeloid-derived suppressor cells (MDSC) is emerging in transplantation. An expansion of myeloid progenitor cells with suppressive capacity has been reported to occur as a bystander phenomenon in the course of allogeneic hematopoietic stem cell transplantation (allo-HSCT) protocols, particularly, in mice during bone marrow chimerism induction and in human stem cell donors during G-CSF-mobilization protocols. Hypothesizing that such 'regulatory myeloid cells' play a role in regulating post-transplant T-cell alloreactivity, we performed a phenotypical and functional characterization of these cells in peripheral blood stem cell grafts of G-CSF-treated donors. We demonstrate that expanding myeloid cells in the peripheral blood of G-CSF-mobilized donors comprise the typical phenotype of the mononuclear and polymorphonuclear MDSC-subtypes that were recently described in cancer patients, and that both MDSC-subsets have the capacity to regulate alloreactive T-cell responses in-vitro. This study provides the basis for investigating the clinical relevance of MDSC and MDSC-subtypes in human allo-HSCT.

Multipotent adult progenitor cells sustain function of ischemic limbs in mice.

Despite progress in cardiovascular research, a cure for peripheral vascular disease has not been found. We compared the vascularization and tissue regeneration potential of murine and human undifferentiated multipotent adult progenitor cells (mMAPC-U and hMAPC-U), murine MAPC-derived vascular progenitors (mMAPC-VP), and unselected murine BM cells (mBMCs) in mice with moderate limb ischemia, reminiscent of intermittent claudication in human patients. mMAPC-U durably restored blood flow and muscle function and stimulated muscle regeneration, by direct and trophic contribution to vascular and skeletal muscle growth. This was in contrast to mBMCs and mMAPC-VP, which did not affect muscle regeneration and provided only limited and transient improvement. Moreover, mBMCs participated in a sustained inflammatory response in the lower limb, associated with progressive deterioration in muscle function. Importantly, mMAPC-U and hMAPC-U also remedied vascular and muscular deficiency in severe limb ischemia, representative of critical limb ischemia in humans. Thus, unlike BMCs or vascular-committed progenitors, undifferentiated multipotent adult progenitor cells offer the potential to durably repair ischemic damage in peripheral vascular disease patients.

Recipient lymphocyte infusion in MHC-matched bone marrow chimeras induces a limited lymphohematopoietic host-versus-graft reactivity but a significant antileukemic effect mediated by CD8+ T cells and natural killer cells.

BACKGROUND: Challenge of MHC-mismatched murine bone marrow chimeras with recipient-type lymphocytes (recipient lymphocyte infusion) produces antileukemic responses in association with rejection of donor chimerism. In contrast, MHC-matched chimeras resist eradication of donor chimerism by recipient lymphocyte infusion. Here, we investigated lymphohematopoietic host-versus-graft reactivity and antileukemic responses in the MHC-matched setting, which is reminiscent of the majority of clinical transplants. DESIGN AND METHODS: We challenged C3H→AKR radiation chimeras with AKR-type splenocytes (i.e. recipient lymphocyte infusion) and BW5147.3 leukemia cells. We studied the kinetics of chimerism using flowcytometry and the mechanisms involved in antileukemic effects using in vivo antibody-mediated depletion of CD8(+) T and NK cells, and intracellular cytokine staining. RESULTS: Whereas control chimeras showed progressive evolution towards high-level donor T-cell chimerism, recipient lymphocyte infusion chimeras showed a limited reduction of donor chimerism with delayed onset and long-term preservation of lower-level mixed chimerism. Recipient lymphocyte infusion chimeras nevertheless showed a significant survival benefit after leukemia challenge. In vivo antibody-mediated depletion experiments showed that both CD8(+) T cells and NK cells contribute to the antileukemic effect. Consistent with a role for NK cells, the proportion of IFN-γ producing NK cells in recipient lymphocyte infusion chimeras was significantly higher than in control chimeras. CONCLUSIONS: In the MHC-matched setting, recipient lymphocyte infusion elicits lymphohematopoietic host-versus-graft reactivity that is limited but sufficient to provide an antileukemic effect, and this is dependent on CD8(+) T cells and NK cells. The data indicate that NK cells are activated as a bystander phenomenon during lymphohematopoietic T-cell alloreactivity and thus support a novel type of NK involvement in anti-tumor responses after post-transplant adoptive cell therapy.

Etanercept improves linear growth and bone mass acquisition in MTX-resistant polyarticular-course juvenile idiopathic arthritis.

OBJECTIVES: Chronic inflammation in juvenile idiopathic arthritis interferes with linear growth and bone mass acquisition. We prospectively evaluated and compared linear growth and evolution of bone mass acquisition and body composition in MTX-resistant polyarticular-course JIA (polyJIA) patients started on etanercept and in recently diagnosed polyJIA patients started on MTX monotherapy. METHODS: Sixteen MTX-resistant polyJIA patients were given add-on etanercept, eight recently diagnosed polyJIA patients were started on MTX. Patients were evaluated at baseline and at 1, 6, 12 and 18 months with respect to disease activity, linear growth, BMD and body composition. RESULTS: Baseline patient and disease characteristics were similar in both groups. Clinical disease activity (Pediatric ACR30) was equally well controlled in both groups. Growth velocity increased significantly allowing catch-up growth in the etanercept + MTX group only. BMD (lumbar spine Z-score) improved significantly in both groups. A significant increase of bone mineral content and lean:fat mass ratio was seen in the etanercept + MTX group, but not in the MTX group. CONCLUSION: Clinical control of disease activity by etanercept in MTX-refractory polyJIA is associated with rapidly instituted catch-up growth and improvement of bone mineralization and body composition. In recently diagnosed polyJIA patients treated with MTX the relation between clinical response and these parameters was less evident. Preliminary data on serum IL-6 and osteoprotegerin levels indicate that the beneficial effects seen with etanercept therapy may be related to its control of systemic IL-6 production and enhancement of osteoblast activity.

Contribution of regulatory T cells and effector T cell deletion in tolerance induction by costimulation blockade.

Blocking of costimulatory signals for T cell activation leads to tolerance in several transplantation models, but the underlying mechanisms are incompletely understood. We analyzed the involvement of regulatory T cells (Treg) and deletion of alloreactive cells in the induction and maintenance of tolerance after costimulation blockade in a mouse model of graft-vs-host reaction. Injection of splenocytes from the C57BL/6 parent strain into a sublethally irradiated F(1) offspring (C57BL/6 x C3H) induced a GVHR characterized by severe pancytopenia. Treatment with anti-CD40L mAb and CTLA4-Ig every 3 days during 3 wk after splenocyte injection prevented disease development and induced a long-lasting state of stable mixed chimerism (>120 days). In parallel, host-specific tolerance was achieved as demonstrated by lack of host-directed alloreactivity of donor-type T cells in vitro and in vivo. Chimerism and tolerance were also obtained after CD25(+) cell-depleted splenocyte transfer, showing that CD25(+) natural Treg are not essential for tolerance induction. We further show that costimulation blockade results in enhanced Treg cell activity at early time points (days 6-30) after splenocyte transfer. This was demonstrated by the presence of a high percentage of Foxp3(+) cells among donor CD4(+) cells in the spleen of treated animals, and our finding that isolated donor-type T cells at an early time point (day 30) after splenocyte transfer displayed suppressive capacity in vitro. At later time points (>30 days after splenocyte transfer), clonal deletion of host-reactive T cells was found to be a major mechanism responsible for tolerance.

Ablation of proliferating microglia does not affect motor neuron degeneration in amyotrophic lateral sclerosis caused by mutant superoxide dismutase.

Microglial activation is a hallmark of all neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Here, a detailed characterization of the microglial cell population within the spinal cord of a mouse model of familial ALS was performed. Using flow cytometry, we detected three distinct microglial populations within the spinal cord of mice overexpressing mutant superoxide dismutase (SOD1): mature microglial cells (CD11b(+), CD45(low)), myeloid precursor cells (CD11b(+), CD45(int)), and macrophages (CD11b(+), CD45(high)). Characterization of cell proliferation within the CNS of SOD1(G93A) mice revealed that the expansion in microglial cell population is mainly attributable to the proliferation of myeloid precursor cells. To assess the contribution of proliferating microglia in motor neuron degeneration, we generated CD11b-TK(mut-30); SOD1(G93A) doubly transgenic mice that allow the elimination of proliferating microglia on administration of ganciclovir. Surprisingly, a 50% reduction in reactive microglia specifically in the lumbar spinal cord of CD11b-TK(mut-30); SOD1(G93A) doubly transgenic mice had no effect on motor neuron degeneration. This suggests that proliferating microglia-expressing mutant SOD1 are not central contributors of the neurodegenerative process in ALS caused by mutant SOD1.

Variation in dentofacial morphology and occlusion in juvenile idiopathic arthritis subjects: a case-control study.

Juvenile idiopathic arthritis (JIA) can severely disturb facial growth and affect occlusal development. In this case-control study, facial, functional, and occlusal characteristics of 100 JIA patients (35 males and 65 females; age range: 1.7-19.4 years) comprising all subtypes classified according to the revised classification criteria of the International League of Associations for Rheumatology (ILAR) were studied. They were compared with a mixed orthodontic control group (n=32; 12 males and 20 females) and with a Class II division 1 malocclusion group (n=19; eight males and 11 females). The JIA patients and controls were evaluated using clinical assessment, dental pantomograms, lateral cephalograms (LCGs), and dental casts. Compared with the age- and gender-matched mixed orthodontic controls, JIA patients showed a significantly greater prevalence of anterior open bites (AOBs; P<0.05; Wilcoxon matched pairs test). Cephalometrically, a larger mandibular plane (P<0.05) and SNA (P<0.001) angles and a smaller interincisal angle (P<0.001) were found. In comparison with the Class II division 1 controls, JIA patients showed a larger SNA (P<0.001; Wilcoxon matched pairs test) and SNB (P<0.05) angles and smaller lower anterior face heights (LAFHs; P<0.05). No differences were found for the mandibular plane, the gonial and the interincisal angles, or total face height. From this case-control study, it can be concluded that although JIA patients share occlusal characteristics with non-JIA patients with a Class II division 1 malocclusion, they are different with regard to the prevalence of condylar lesions and AOBs, as well as SNA and SNB angles and LAFH.

Solid Tumor-Induced Immune Regulation Alters the GvHD/GvT Paradigm after Allogenic Bone Marrow Transplantation.

Growth of solid tumors is often associated with the development of an immunosuppressive tumor microenvironment (TME). It has been suggested that the influence of the TME may extend beyond the local tumor and results in systemic immunosuppression. Here, we utilize two murine cancer models to explore the influence of solid tumors on the occurrence of alloreactivity-driven GvHD and graft-versus-solid tumor (GvT) effects following MHC-mismatched allogeneic bone marrow transplantation (allo-BMT). Melanoma- or colon carcinoma-bearing C57BL/6 mice did not develop GvHD after BMT even when the bone marrow inoculum was supplemented with donor-type splenocytes. This protection against GvHD required the presence of tumors because its resection prior to allo-BMT promptly resulted in development of GvHD. In addition, tumor-bearing mice given T-cell-depleted allo-BMT (allo-TCD-BMT) failed to develop GvHD and also showed significantly stronger GvT effects than mice given allo-BMT. The GvT effects in allo-TCD-BMT recipients were associated with profound changes in tumor-infiltrating cells compared with that in allo-BMT recipients, with significantly reduced donor-derived regulatory T cells (Treg), increased cytotoxic effector (IFNγhi) CD8 T cells, and increased M1 macrophages (iNOShi, arginaselo, and IL10lo); the use of macrophage-depleted bone marrow abrogated the GvT effects. Collectively, these results indicate that the presence of M1 macrophages may disrupt the generation of donor-type Treg cells so that the immunomodulatory effect of the TME can affect systemic immunity. SIGNIFICANCE: These findings show that cells such as T cells or macrophages in the bone marrow inoculum may interfere with the systemic and local immune reactivity against tumors.

Autologous and allogeneic hematopoietic stem cell transplantation for Multiple Sclerosis: perspective on mechanisms of action.

Multiple Sclerosis (MS) is a frequent demyelinating immune-mediated disease of the central nervous system (CNS) that affects principally young adults and leads to severe physical and cognitive impairment. The current standard treatment makes use of the immune modulators beta-interferon, glatiramer acetate and natalizumab, or immunosuppressants such as mitoxantrone. However, these agents are only partially effective and in a number of patients fail to achieve satisfactory disease control. Autologous hematopoietic stem cell transplantation (HSCT) is being explored in the treatment of severe MS as a means of delivering high-dose immunosuppression followed by 'rescue' of the immuno-hematopoietic system with autologous HSC. The potential therapeutic benefit is based on the concept of so-called 'resetting' the immune system. The use of allogeneic HSCT as a possible therapeutic approach for severe MS is inspired by case reports of MS patients that underwent allogeneic HSCT for a concomitant hematological malignancy, and subsequently is supported by data from rodent models of MS. Allogeneic HSCT may offer specific therapeutic effects, such as the replacement of the autoreactive immune compartment by healthy allogeneic cells and the development of a graft-versus-autoimmunity (GVA) effect. Here, we review the currently available experimental and clinical evidence to support the role of autologous and allogeneic HSCT in MS.

Late CD8+ T cell-dependent xenoantibody production in innate tolerant nude rats after hamster islet grafting but not after hamster heart grafting.

BACKGROUND: Xenograft rejection can be provoked by both the innate and adaptive immune compartments and close reciprocal interactions exist between these two systems. We investigated the interdependent roles of T and B lymphocytes in vascularized (heart) and cellular (islet) xenograft rejection in a model with established xeno-nonreactivity of the innate immune system. METHODS: Specific innate xenotolerance was induced in nude rats bearing either a hamster heart or a hamster pancreatic islet graft by a tolerizing regimen consisting of donor antigen infusion, temporary natural killer cell depletion and a 4-week administration of leflunomide. One month after transplantation, syngeneic CD4 and CD8 T cells were adoptively transferred. RESULTS: Both vascular and cellular xenografts were rejected after CD4 T cell reconstitution, corresponding with production of high IgM and IgG xenoantibody titers. Deposition of xenoantibodies and complement was seen in the heart but not in the islet xenografts. After infusion of CD8 T cells, xenohearts underwent a delayed type of rejection without xenoantibody production and xenoislets were not rejected. In xenoislet recipients, CD8 dependent B cells were not tolerized, resulting in the production of IgG xenoantibodies belonging to Th2-dependent isotypes, known not to cause graft rejection, and deposited at the graft implantation site. CONCLUSIONS: We conclude that distinct mechanisms of immune activation underlie xenogeneic reactions against vascular and cellular grafts.

Occurrence of autoimmunity after xenothymus transplantation in T-cell-deficient mice depends on the thymus transplant technique.

Xenothymus transplantation under the kidney capsule in athymic rodents frequently leads to multiorgan autoimmunity. Herein, we explore whether this is an intrinsic risk of xenothymus grafting or whether it depends on the transplant technique. We developed a new technique of "venous pouch" thymus grafting (heart-xenothymus) and compared this with the conventional kidney subcapsular technique (kidney-xenothymus) in a rat-into-nude-mouse model. Whereas lethal autoimmunity developed in 90% of kidney-xenothymus recipients, all heart-xenothymus grafted mice remained completely healthy. Autoimmunity in heart-xenothymus recipients was absent despite a significantly improved T-cell generation and was associated with significantly higher CD4+CD25+ T-cell frequencies and CD4+CD25+ cell Foxp3 mRNA levels than those observed in kidney-xenothymus recipients. In conclusion, we describe a novel vascular pouch technique of xenothymus transplantation that prevents the development of autoimmunity in nude mice. Our data further suggest that prevention of autoimmunity is related to a superior development of regulatory T-cells.

Selective expansion of marginal zone B cells in Emicro-API2-MALT1 mice is linked to enhanced IkappaB kinase gamma polyubiquitination.

The translocation t(11;18)(q21;q21) that generates an API2-MALT1 fusion protein is the most common structural abnormality among the genetic defects reported in mucosa-associated lymphoid tissue (MALT)-type lymphomas, and its presence correlates with the apparent lack of further genetic instability or chromosomal imbalances. Hence, constitutive nuclear factor-kappaB (NF-kappaB) activation induced by the API2-MALT1 fusion protein is considered essential for B-cell transformation. To examine its role in B-cell development and lymphomagenesis, Emu-API2-MALT1 transgenic mice were produced. Our data show that expression of the API2-MALT1 fusion protein alone is not sufficient for the development of lymphoma masses within 50 weeks. Nevertheless, API2-MALT1 expression affected B-cell maturation in the bone marrow and triggered the specific expansion of splenic marginal zone B cells. Polyubiquitination of IkappaB kinase gamma (IKKgamma), indicative for enhanced NF-kappaB activation, was increased in splenic lymphocytes and promoted the survival of B cells ex vivo. In addition, we show that the API2-MALT1 fusion resided in the cholesterol- and sphingolipid-enriched membrane microdomains, termed lipid rafts. We provide evidence that association of the MALT1 COOH terminal with the lipid rafts, which is mediated by the API2 portion, is sufficient to trigger NF-kappaB activation via enhanced polyubiquitination of IKKgamma. Taken together, these data support the hypothesis that the API2-MALT1 fusion protein can contribute to MALT lymphoma formation via increased NF-kappaB activation.

Recipient and donor cells in the graft-versus-solid tumor effect: It takes two to tango.

Allogeneic hematopoietic stem cell transplantation (alloHSCT) produces -similar to the long-established graft-versus-leukemia effect- graft-versus-solid-tumor effects. Clinical trials reported response rates of up to 53%, occurring mostly but not invariably in association with full donor chimerism and/or graft-versus-host disease. Although donor-derived T cells are considered the principal effectors of anti-tumor immunity after alloHSCT or donor leukocyte infusion (DLI), growing evidence indicate that recipient-derived immune cells may also contribute. Whereas the role of recipient-derived antigen-presenting cells in eliciting graft-versus-host reactions and priming donor T cells following DLI is well known, resulting inflammatory responses may also break tolerance of recipient effector cells towards the tumor. Additionally, mouse studies indicated that post-transplant recipient leukocyte infusion produces anti-leukemia and anti-solid-tumor effects that were exclusively mediated by recipient-type effector cells, without graft-versus-host disease. Here, we review current preclinical and clinical evidence on graft-versus-solid-tumor effects and growing evidence on the effector role of recipient-derived immune cells in the anti-tumor effect of alloHSCT.

Experimental and clinical approaches for optimization of the graft-versus-leukemia effect.

The goal of allogeneic (allo)-hematopoietic stem-cell transplantation (HSCT) in the treatment of hematologic malignancies is to harness the graft-versus-leukemia (GVL) effect, while minimizing the risk of graft-versus-host disease (GVHD). Allo-HSCT research has focused on the GVL target antigens and effector mechanisms, and on potential approaches to exploit GVL independently of GVHD. Donor lymphocyte infusion (DLI) achieves the most powerful anti-leukemic responses, and this approach is often used in combination with nonmyeloablative transplant regimens to optimize GVL and reduce GVHD. Serial, dose-escalating, and CD8(+) T-cell-depleted DLI have been introduced into clinical practice, while other variants of DLI have so far been explored only in animal models. The role of naturally occurring regulatory T cells in transplantation tolerance is being increasingly acknowledged, and murine studies indicate the potential ability of T cells to regulate GVHD while maintaining GVL. Experimental and clinical studies have demonstrated the importance of host-type chimerism, particularly for antigen-presenting cells, in determining the occurrence of DLI-induced GVL. Murine studies could assist in the development of clinical strategies targeted at antigen-presenting cells. Clinical studies exploiting natural killer-cell-mediated antitumor reactivity in the context of killer inhibitory receptor-ligand-mismatched allo-HSCT have provided promising results.

Can graft-versus-leukemia reactivity be dissociated from graft-versus-host disease?

Dissociation of graft-versus-leukemia (GvL). effects from graft-versus-host disease (GvHD) is the ultimate goal of allogeneic hematopoietic stem cell transplantation (alloHSCT) in the treatment of hematological malignancies. The pivotal role of donor T cells in both anti-leukemic and anti-host reactivity of allogeneic stem cell grafts has been known since the first transplants for fatal leukemia were performed over 25 years ago. Growing understanding of the T cell-mediated GvL response has revealed the importance of host-type antigen-presenting cells and the capacity of adoptively transferred donor T cells in inducing anti-leukemic responses, and has led to a re-evaluation of the relative roles of the pre-transplant conditioning regimen and the allogeneic stem cell graft. Key advances in clinical practice such as reduced-intensity stem cell transplantation and donor lymphocyte infusions are now routinely applied and allow for the induction of potent antileukemic effects, while GvHD can to some extent be controlled. Other strategies to separate T cell-mediated antileukemic effects from GvHD are antigen-specific adoptive T cell-therapy and recipient lymphocyte infusion (RLI) and these are in an experimental stage. Importantly, a role for alloreactive natural killer cells in mediating GvL without GvHD has emerged in patient studies of MHC haplotype-mismatched alloHSCT. Finally, experimental studies indicate that naturally occurring regulatory T cells may differentially affect GvHD and GvL.

Epilepsy and the immune system: is there a link?

The concept that the immune system plays a role in the epileptogenic process of some epileptic syndromes was first proposed more than 20 years ago. Since then, numerous studies have reported on the existence of a variety of immunological alterations in epileptic patients, on the observation of favourable responses of refractory epilepsy syndromes to immunomodulatory treatment, and on the association of certain well-known immune-mediated disease states with epilepsy. This review comprehensively recapitulates the currently available evidence supporting or arguing against the possible involvement of the immune system in the pathogenesis of certain types of epilepsy. It is concluded that an abundance of facts is in support of this concept and that further studies should be directed at substantiating the pathogenic significance of (auto)immune responses in certain types of epilepsy. Current progress in the functional and molecular immunological research techniques will indisputably contribute to the elucidation of this link.