Functions of natural killer cells.

Natural killer (NK) cells are effector lymphocytes of the innate immune system that control several types of tumors and microbial infections by limiting their spread and subsequent tissue damage. Recent research highlights the fact that NK cells are also regulatory cells engaged in reciprocal interactions with dendritic cells, macrophages, T cells and endothelial cells. NK cells can thus limit or exacerbate immune responses. Although NK cells might appear to be redundant in several conditions of immune challenge in humans, NK cell manipulation seems to hold promise in efforts to improve hematopoietic and solid organ transplantation, promote antitumor immunotherapy and control inflammatory and autoimmune disorders.

Donor-Specific Human Leukocyte Antigen Antibody Formation After Distal Tibia Allograft and Subsequent Graft Resorption.

The association between donor-specific human leukocyte antigen (HLA) antibody formation and small bone allograft resorption has not been studied. We present the case of a patient treated for glenoid bone loss using a distal tibial allograft with Bankart repair who formed donor-specific HLA antibodies against the allograft and had subsequent graft resorption. X-ray and computed tomography (CT) scans were performed before and after surgery at standard checkpoints. Patient blood and serum samples were collected before and after surgery for HLA typing and HLA antibody testing. Human leukocyte antigen antibodies against the donor-specific HLA-A2 antigens were identified 6 weeks after surgery and were still detected at 5 months after surgery. At 6 months after surgery, a CT arthrogram revealed significant graft resorption. This case shows a temporal correlation between HLA antibody formation and clinical findings, potentially suggesting an association between HLA antibody formation and graft resorption. Further study is required to confirm this.

IL17A and IL17F genes polymorphisms are associated with histopathological changes in transplanted kidney.

BACKGROUND: Interleukin 17 is a proinflammatory cytokine involved in immune response after allograft transplantation. IL-17 family of proinflammatory cytokines includes IL-17A and IL-17F. Previous studies have demonstrated that the rs2275913 IL17A and the rs11465553 IL17F gene polymorphism are associated with kidney allograft function. Because of the association between these polymorphisms and post-transplant immune response, we assume that these single nucleotide polymorphisms may affect morphological structure of transplanted kidney. The aim of this study was to examine the association of rs2275913 IL17A and rs2397084, rs11465553 and rs763780 IL17F gene polymorphisms with histopathological changes in transplanted kidney biopsies such as: glomerulitis, tubulitis, arteritis, cell infilitration and fibrosis. METHODS: The study enrolled 82 patients after renal graft transplantation in whom a kidney biopsy was performed because of impaired graft function. The rs2397084 T > C (Glu126Gly), rs11465553 G > A (Val155Ile) and rs763780 T > C (His167Arg) polymorphisms within the IL17F gene and the rs2275913 A > G (- 197 A > G) polymorphism within the IL17A gene promoter were genotyped using TaqMan genotyping assays on a 7500 FAST Real-Time PCR System (Applied Biosystems, USA). RESULTS: There was a significant association between the rs2275913 IL17A gene polymorphism and the grade of tubulitis, which was more severe among patients with the A allele, compared to recipients with the GG genotype (GG vs. AG + AA, P = 0.02), and with the grade of arteriolar hyaline thickening and mesangial matrix increase, which were more severe among patients with the G allele compared to recipients with the AA genotype (AA vs. AG + GG, P = 0.01 and P = 0.04, respectively). Tubular atrophy and interstitial fibrosis were more severe among individuals with the C allele at the rs763780 IL17F gene polymorphism (TT vs. TC, P = 0.09 and P = 0.017, respectively). However, it should be taken into account that the statistical significance was achieved without correction for multiple testing, and no significant association would remain significant after such correction. CONCLUSIONS: The results of this study may suggest a possible association between the rs2275913 IL17A and rs2275913 IL17A gene polymorphisms and some histopathological changes in transplanted kidney biopsies.

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.

Haploidentical hematopoietic transplantation for the cure of leukemia: from its biology to clinical translation.

The present review describes the biology of human leukocyte antigen haplotype mismatched ("haploidentical") transplantation, its translation to clinical practice to cure leukemia, and the results of current transplantation protocols. The 1990s saw what had been major drawbacks of haploidentical transplantation, ie, very strong host-versus-graft and graft-versus-host alloresponses, which led respectively to rejection and graft-versus-host disease (GVHD), being overcome through transplantation of a "mega-dose" of T cell-depleted peripheral blood hematopoietic progenitor cells and no posttransplant pharmacologic immunosuppression. The absence of posttransplant immunosuppression was an opportunity to discover natural killer cell alloreactions that eradicated acute myeloid leukemia and improved survival. Furthermore, it also unveiled the benefits of transplantation from mother donors, a likely consequence of the mother-to-child interaction during pregnancy. More recent transplantation protocols use unmanipulated (without ex vivo T-cell depletion) haploidentical grafts combined with enhanced posttransplant immunosuppression to help prevent GVHD. Unmanipulated grafts substantially extended the use of haploidentical transplantation with results than even rival those of matched hematopoietic transplantation. In T cell-depleted haploidentical transplantation, recent advances were made by the adoptive transfer of regulatory and conventional T cells.

Evaluation of engraftment syndrome in children following full-matched related donor hematopoietic stem cell transplantations.

The term "ES" has been widely used for describing a clinical condition consisting of skin rash, fever, and weight gain that occur during neutrophil recovery period following HSCT. In this study, the incidence, clinical features, risk factors, and outcomes of ES were evaluated in 169 children following allogeneic HSCT from full-matched related donor according to the Spitzer criteria. Seventeen patients (10.1%) presented with clinical conditions suggesting ES. In both univariate and multivariate analysis underlying malignant disease and early release of monocytes to the PB, and in univariate analysis using only CsA for GVHD prophylaxis were found to be the significant risk factors for the development of ES. Patients with ES experienced significantly higher incidence of acute and chronic GVHD and propensity toward a higher rate of TRM. OS did not differ between the patient groups. Thirteen of 17 patients received steroid therapy, and all but one patient responded to therapy. Monitoring for early detection of ES and early intervention with steroid therapy is the key for recovery. The most crucial approach for this purpose mainly is to find out and use the most useful and feasible diagnostic criteria for routine medical practice.

Targeting the Innate Immune Response to Improve Cardiac Graft Recovery after Heart Transplantation: Implications for the Donation after Cardiac Death.

Heart transplantation (HTx) is the ultimate treatment for end-stage heart failure. The number of patients on waiting lists for heart transplants, however, is much higher than the number of available organs. The shortage of donor hearts is a serious concern since the population affected by heart failure is constantly increasing. Furthermore, the long-term success of HTx poses some challenges despite the improvement in the management of the short-term complications and in the methods to limit graft rejection. Myocardial injury occurs during transplantation. Injury initiated in the donor as result of brain or cardiac death is exacerbated by organ procurement and storage, and is ultimately amplified by reperfusion injury at the time of transplantation. The innate immune system is a mechanism of first-line defense against pathogens and cell injury. Innate immunity is activated during myocardial injury and produces deleterious effects on the heart structure and function. Here, we briefly discuss the role of the innate immunity in the initiation of myocardial injury, with particular focus on the Toll-like receptors and inflammasome, and how to potentially expand the donor population by targeting the innate immune response.

Dendritic cells and innate immunity in kidney transplantation.

This review summarizes emerging concepts related to the roles of dendritic cells (DCs) and innate immunity in organ transplant rejection. First, it highlights the primary role that recipient, rather than donor, DCs have in rejection and reviews their origin and function in the transplanted kidney. Second, it introduces the novel concept that recognition of allogeneic non-self by host monocytes (referred to here as innate allorecognition) is necessary for initiating rejection by inducing monocyte differentiation into mature, antigen-presenting DCs. Both concepts provide opportunities for preventing rejection by targeting monocytes or DCs.

Imaging Tolerance Induction in the Classic Medawar Neonatal Mouse Model: Active Roles of Multiple F1-Donor Cell Types.

The immature immune system is uniquely susceptible to tolerance induction and thus an attractive target for immunomodulation strategies for organ transplantation. Newborn mice injected with adult semi-allogeneic lymphohematopoietic cells accept transplants without immunosuppressive drugs. Early in vivo/in situ events leading to neonatal tolerance remain poorly understood. Here, we show by whole body/organ imaging that injected cells home to lymphoid organs and liver where various F1-donor cell types selectively alter neonatal immunity. In host thymus, F1-donor dendritic cells (DC) interact with developing thymocytes and regulatory T cells suggesting a role in negative selection. In spleen and lymph nodes, F1-donor regulatory T/B cells associate with host alloreactive cells and by themselves prolong cardiac allograft survival. In liver, F1-donor cells give rise to albumin-containing hepatocyte-like cells. The neonatal immune system is lymphopenic, Th-2 immunodeviated and contains immature DC, suggesting susceptibility to regulation by adult F1-donor cells. CD8a T cell inactivation greatly enhances chimerism, suggesting that variable emerging neonatal alloreactivity becomes a barrier to tolerance induction. This comprehensive qualitative imaging study systematically shows contribution of multiple in vivo processes leading simultaneously to robust tolerance. These insights into robust tolerance induction have important implications for development of strategies for clinical application.

Combined induction therapy with rabbit antithymocyte globulin and rituximab in highly sensitized renal recipients.

Compared to non-sensitized renal transplant recipients, patients with preformed alloantibodies are at greater risk of cellular and humoral rejection and premature graft failure. We explored the effects of adding B-cell depleting agent (rituximab) to standard rabbit anti-thymocyte globulin (rATG) induction regimen for patients with panel reactive antibody levels >50%. Following induction therapy, 14 recipients were given two doses of rituximab (375 mg/m(2)) within the first month post-transplantation. Their long-term outcomes were compared to a historical control group of 23 recipients who received rATG alone. Graft survival at 5 years was superior with combination therapy compared to induction therapy alone (92.9 versus 48.3%, respectively, p = 0.02). While 30% of the rATG alone group experienced cellular rejection and 26% humoral rejection, none of rituximab plus rATG renal transplant recipients group had rejection. Thus, addition of rituximab to rATG provided superior outcomes to rATG alone. This combination induction therapy should be considered for a high-risk population.

In vitro cytokine changes after pediatric liver transplantation.

BACKGROUND: Patients with chronic liver disease have been shown to have impaired immune statuses. Liver transplantation (LT) is the standard treatment for end-stage liver disease patients and immunosuppressive drugs are commonly used to prevent graft rejection. There is an increasing evidence of de novo food allergies post LT. OBJECTIVE: To investigate the cytokine response of peripheral blood mononuclear cells (PBMCs) of pediatric LT recipients before and six months after transplantation. METHOD: PBMCs collected before and six months after LT were stimulated with phytohemagglutinin (PHA), beta-lactoglobulin (BLG), tacrolimus (Tac), dexamethasone (Dex), and a combination of BLG and Dex (B+D), BLG and Tac (B+T), BLG and Tac plus Dex (B+T+D). Culture supernatants were measured for IL-5, IFN-γ and IL-10. Blood for liver function tests, complete blood counts, total IgE and specific IgE (sIgE) to cow's milk were recorded. RESULTS: A total of five pediatric LT recipients were enrolled in the study. There were no food allergy cases. Total IgE and sIgE to cow's milk decreased significantly after LT. After transplantation, there was a significant increase in IL-5, IFN-γ and IL-10 in culture supernatants of PHA-stimulated PBMCs. Among different stimulations in post transplantation's PBMCs, the level of IL-5 significantly increased in B+D was suppressed with the combination of B+T+D. The level of IL-10 significantly increased in all conditions containing BLG both before and after transplantation. CONCLUSION: There was an improvement of the in vitro-cytokine responses after liver transplantations. Immunosuppressive drugs used in post transplantation had an effect on the cytokine responses.

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.

Donor CD8 T cells and IFN-gamma are critical for sex-based differences in donor CD4 T cell engraftment and lupus-like phenotype in short-term chronic graft-versus-host disease mice.

The transfer of unfractionated DBA/2J (DBA) splenocytes into B6D2F(1) (DBA → F(1)) mice results in greater donor CD4 T cell engraftment in females at day 14 that persists long-term and mediates greater female lupus-like renal disease. Although donor CD8 T cells have no demonstrated role in lupus pathogenesis in this model, we recently observed that depletion of donor CD8 T cells prior to transfer eliminates sex-based differences in renal disease long-term. In this study, we demonstrate that greater day 14 female donor CD4 engraftment is also critically dependent on donor CD8 T cells. Male DBA → F(1) mice exhibit stronger CD8-dependent day 8-10 graft-versus-host (GVH) and counter-regulatory host-versus-graft (HVG) responses, followed by stronger homeostatic contraction (days 10-12). The weaker day 10-12 GVH and HVG in females are followed by persistent donor T cell activation and increasing proliferation, expansion, and cytokine production from days 12 to 14. Lastly, greater female day 14 donor T cell engraftment, activation, and cytokine production were lost with in vivo IFN-γ neutralization from days 6 to 14. We conclude the following: 1) donor CD8 T cells enhance day 10 proliferation of donor CD4 T cells in both sexes; and 2) a weaker GVH/HVG in females allows prolonged survival of donor CD4 and CD8 T cells, allowing persistent activation. These results support the novel conclusion that sex-based differences in suboptimal donor CD8 CTL activation are critical for shaping sex-based differences in donor CD4 T cell engraftment at 2 wk and lupus-like disease long-term.

The significance of the host inflammatory response on the therapeutic efficacy of cell therapies utilising human adult stem cells.

Controlling the fate of implanted hMSCs is one of the major drawbacks to be overcome to realize tissue engineering strategies. In particular, the effect of the inflammatory environment on hMSCs behaviour is poorly understood. Studying and mimicking the inflammatory process in vitro is a very complex and challenging task that involves multiple variables. This research addressed the questions using in vitro co-cultures of primary derived hMSCs together with human peripheral blood mononucleated cells (PBMCs); the latter are key agents in the inflammatory process. This work explored the in vitro phenotypic changes of hMSCs in co-culture direct contact with monocytes and lymphocytes isolated from blood using both basal and osteogenic medium. Our findings indicated that hMSCs maintained their undifferentiated phenotype and pluripotency despite the contact with PBMCs. Moreover, hMSCs demonstrated increased proliferation and were able to differentiate specifically down the osteogenic lineage pathway. Providing significant crucial evidence to support the hypothesis that inflammation and host defence mechanisms could be utilised rather than avoided and combated to provide for the successful therapeutic application of stem cell therapies.

Invariant NKT cells are required for antitumor responses induced by host-versus-graft responses.

Based on clinical observations, we have previously shown in a murine model that recipient leukocyte infusion (RLI) induces a host-versus-graft reaction in mixed bone marrow chimeras and that rejection of donor cells leads to a specific antitumor response against recipient malignancies. This response is dependent on T cells and IFN-gamma. We investigated the role of NKT cells (NKTs) in this phenomenon. Depletion of recipient NK1.1(+) cells led to loss of an anti-tumor effect induced by RLI in mixed bone marrow chimeras. In recipients specifically lacking host invariant NKT cells (iNKTs), RLI did not induce an antitumor effect, indicating a critical role for recipient iNKTs. Conversely, specific activation of iNKTs enhanced the anti-tumor effect induced by RLI. Following RLI, recipient iNKTs, NK cells, dendritic cells (DCs), and CD8 T cells were activated. CD8 T cells were the major producers of IFN-gamma. Lack of recipient iNKTs resulted in failure of activation of NK cells and DCs by RLI. Our studies demonstrate a central role for iNKTs in promoting RLI-induced anti-tumor effects and suggest that this pathway involved promotion of the activation of recipient NK cells and DCs.

Uptake of CCR7 and acquisition of migratory properties by human KIR+ NK cells interacting with monocyte-derived DC or EBV cell lines: regulation by KIR/HLA-class I interaction.

C-C chemokine receptor type 7 (CCR7) is a chemokine receptor playing a pivotal role in the induction of human natural killer (NK)-cell migration to lymph nodes. We show that "licensed" peripheral blood killer immunoglobulin-like receptor-positive (KIR(+)) NK-cell populations, as well as KIR(+) NK-cell clones, de novo express CCR7 upon coculture with mature dendritic cells (mDCs) or Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines. As a consequence, they become capable of migrating in response to the CCR7-specific chemokines C-C chemokine ligand (CCL)-19 and/or CCL21. The acquisition of CCR7 by NK cells requires direct cell-to-cell contact, is detectable within a few minutes, and is due to receptor uptake from CCR7(+) cells. This mechanism is tightly regulated by KIR-mediated recognition of human leukocyte antigen (HLA) class I as well as by adhesion molecules including leukocyte function-associated antigen 1 (LFA-1) and CD2. Analysis of NK-cell clones revealed that alloreactive (KIR-ligand mismatched) but not autologous NK cells acquire CCR7. These data have important implications in haploidentical hematopoietic stem cell transplantation (HSCT), in which alloreactive NK cells may acquire the ability to migrate to secondary lymphoid compartments (SLCs), where they can kill recipient antigen-presenting cells (APCs) and T cells thus preventing graft-versus-host (and host-versus-graft) reactions.

Histopathologic Features of Antibody Mediated Rejection: The Banff Classification and Beyond.

Antibody mediated rejection (ABMR) in the kidney can show a wide range of clinical presentations and histopathologic patterns. The Banff 2019 classification currently recognizes four diagnostic categories: 1. Active ABMR, 2. Chronic active ABMR, 3. Chronic (inactive) ABMR, and 4. C4d staining without evidence of rejection. This categorization is limited in that it does not adequately represent the spectrum of antibody associated injury in allograft, it is based on biopsy findings without incorporating clinical features (e.g., time post-transplant, de novo versus preformed DSA, protocol versus indication biopsy, complement inhibitor drugs), the scoring is not adequately reproducible, and the terminology is confusing. These limitations are particularly relevant in patients undergoing desensitization or positive crossmatch kidney transplantation. In this article, I discuss Banff criteria for these ABMR categories, with a focus on patients with pre-transplant DSA, and offer a framework for considering the continuum of allograft injury associated with donor specific antibody in these patients.

The Impact of Inflammation on the Immune Responses to Transplantation: Tolerance or Rejection?

Transplantation (Tx) remains the optimal therapy for end-stage disease (ESD) of various solid organs. Although alloimmune events remain the leading cause of long-term allograft loss, many patients develop innate and adaptive immune responses leading to graft tolerance. The focus of this review is to provide an overview of selected aspects of the effects of inflammation on this delicate balance following solid organ transplantation. Initially, we discuss the inflammatory mediators detectable in an ESD patient. Then, the specific inflammatory mediators found post-Tx are elucidated. We examine the reciprocal relationship between donor-derived passenger leukocytes (PLs) and those of the recipient, with additional emphasis on extracellular vesicles, specifically exosomes, and we examine their role in determining the balance between tolerance and rejection. The concept of recipient antigen-presenting cell "cross-dressing" by donor exosomes is detailed. Immunological consequences of the changes undergone by cell surface antigens, including HLA molecules in donor and host immune cells activated by proinflammatory cytokines, are examined. Inflammation-mediated donor endothelial cell (EC) activation is discussed along with the effect of donor-recipient EC chimerism. Finally, as an example of a specific inflammatory mediator, a detailed analysis is provided on the dynamic role of Interleukin-6 (IL-6) and its receptor post-Tx, especially given the potential for therapeutic interdiction of this axis with monoclonal antibodies. We aim to provide a holistic as well as a reductionist perspective of the inflammation-impacted immune events that precede and follow Tx. The objective is to differentiate tolerogenic inflammation from that enhancing rejection, for potential therapeutic modifications. (Words 247).

Immunosuppression for liver transplantation.

In the last few decades liver transplantation (LTx) has become a reliable life-saving procedure for patients with chronic end-stage liver diseases. LTx has an outstanding success rate in the first few years after allografting, especially considering that many patients are on the brink of survival at the time of transplantation. The success of LTx is owed to the pioneers who developed the surgical procedures and to researchers who discovered the medications to help prevent immunological rejection of allografts. However, several problems continue to impose serious limits on LTx today, including a shortage of donor livers, recurrence of disease (eg, hepatitis, hepatocellular cancer), preservation of long-term allograft function and the side effects of anti-rejection drugs. While the dilemma of organ shortage is not a focus of this review, we will address the latter issues as they relate to the "oldest" and "newest" approaches to immunosuppression, and discuss the prospect that recipients could potentially be made immunologically tolerant to liver transplants. Due to the critical shortage of organs, new strategies to preserve transplanted liver allografts for the longest possible time are of paramount importance.

[Indications and management of hematologic microtransplantation: Recommendations of the French Society of Bone Marrow transplantation and cellular Therapy (SFGM-TC)]. / Atelier d'harmonisations 2019 : indications et organisation d'une microtransplantation de cellules souches hématopoïétiques.

Microtransplantation (MT) is based on injection of HLA-mismatched G-CSF mobilized hematopoietic stem cells, in combination with chemotherapy but without use of conditioning regimen nor immunosuppressive drugs. As a result, a transient microchimerism is induced without engraftment. Its efficacy relies both on host immune system stimulation (recipient versus tumor) and on a graft versus tumor effect. Data are scarce and concern mostly Asian patients with acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (HR-MDS). In comparison to conventional treatment without MT, higher complete remission rates and longer disease free survival and overall survival have been reported. Safety seems acceptable. The most frequent adverse event is non-severe cytokine release syndrome. Risk of GVHD remains very low. Here, we summarize the published data and detail the practical aspects of the procedure. Current data are not strong enough to provide recommendations on indications. Nevertheless, it seems reasonable to propose MT to patients with AML or HR-MDS, regardless of age, presenting an indication for allogeneic stem cell transplantation but ineligible for it. MT is still under investigation and rather be proposed within clinical trials.