Memory T cells that are specific for alloantigen can arise from a variety of stimuli, ranging from direct allogeneic sensitization from prior transplantation, blood transfusion, or pregnancy to the elicitation of pathogen-specific T cells that are cross-reactive with alloantigen. Regardless of the mechanism by which they arise, alloreactive memory T cells possess key metabolic, phenotypic, and functional properties that render them distinct from naive T cells. These properties affect the immune response to transplantation in 2 important ways: first, they can alter the speed, location, and effector mechanisms with which alloreactive T cells mediate allograft rejection, and second, they can alter T-cell susceptibility to immunosuppression. In this review, we discuss recent developments in understanding these properties of memory T cells and their implications for transplantation.

Hematopoietic chimerism remains the most promising strategy to bring transplantation tolerance into clinical routine. The concept of chimerism-based tolerance aims to extend the recipient's mechanisms of self-tolerance (ie, clonal deletion, anergy, and regulation) to include the tolerization of donor antigens that are introduced through the cotransplantation of donor hematopoietic cells. For this to be successful, donor hematopoietic cells need to engraft in the recipient at least temporarily. Three pioneering clinical trials inducing chimerism-based tolerance in kidney transplantation have been published to date. Within this review, we discuss the mechanisms of tolerance that are associated with the specific therapeutic protocols of each trial. Recent data highlight the importance of regulation as a mechanism that maintains tolerance. Insufficient regulatory mechanisms are also a likely explanation for situations of tolerance failure despite persisting donor chimerism. After decades of preclinical development of chimerism protocols, mechanistic data from clinical trials have recently become increasingly important. Better understanding of the required mechanisms for tolerance to be induced in humans will be a key to design more reliable and less invasive chimerism protocols in the future.

Hematopoietic stem cell transplantation (HSCT) has many potential applications beyond current standard indications, including treatment of autoimmune disease, gene therapy, and transplant tolerance induction. However, severe myelosuppression and other toxicities after myeloablative conditioning regimens have hampered wider clinical use. To achieve donor hematopoietic stem cell (HSC) engraftment, it appears essential to establish niches for the donor HSCs by depleting the host HSCs. To date, this has been achievable only by nonselective treatments such as irradiation or chemotherapeutic drugs. An approach that is capable of more selectively depleting host HSCs is needed to widen the clinical application of HSCT. Here, we show in a clinically relevant nonhuman primate model that selective inhibition of B cell lymphoma 2 (Bcl-2) promoted hematopoietic chimerism and renal allograft tolerance after partial deletion of HSCs and effective peripheral lymphocyte deletion while preserving myeloid cells and regulatory T cells. Although Bcl-2 inhibition alone was insufficient to induce hematopoietic chimerism, the addition of a Bcl-2 inhibitor resulted in promotion of hematopoietic chimerism and renal allograft tolerance despite using only half of the dose of total body irradiation previously required. Selective inhibition of Bcl-2 is therefore a promising approach to induce hematopoietic chimerism without myelosuppression and has the potential to render HSCT more feasible for a variety of clinical indications.

Lymph node (LN)-resident lymphatic endothelial cells (LEC) mediate peripheral tolerance by self-antigen presentation on MHC-I and constitutive expression of T-cell inhibitory molecules, including PD-L1 (CD274). Tumor-associated LECs also upregulate PD-L1, but the specific role of lymphatic PD-L1 in tumor immunity is not well understood. In this study, we generated a mouse model lacking lymphatic PD-L1 expression and challenged these mice with two orthotopic tumor models, B16F10 melanoma and MC38 colorectal carcinoma. Lymphatic PD-L1 deficiency resulted in consistent expansion of tumor-specific CD8⁺ T cells in tumor-draining LNs in both tumor models, reduced primary tumor growth in the MC38 model, and increased efficacy of adoptive T-cell therapy in the B16F10 model. Strikingly, lymphatic PD-L1 acted primarily by inducing apoptosis in tumor-specific CD8⁺ central memory T cells. Overall, these findings demonstrate that LECs restrain tumor-specific immunity via PD-L1, which may explain why some patients with cancer without PD-L1 expression in the tumor microenvironment still respond to PD-L1/PD-1-targeted immunotherapy. SIGNIFICANCE: A new lymphatic-specific PD-L1 knockout mouse model reveals that lymphatic endothelial PD-L1 expression reduces tumor immunity, inducing apoptosis in tumor-specific CD8⁺ central memory cells in tumor-draining lymph nodes.

Transplantation is the most effective, and sometimes the only resort for end-stage organ failure. However, allogeneic graft suffers greatly from lymphocyte-mediated immunorejection, which bears close relationship with a hyperactivation of endoplasmic reticulum (ER) stress response in host lymphocytes, especially in CD8⁺ T cells (T-8). Therefore, regulating lymphocytic ER unfolded protein response (UPR) might be a potential therapeutic breakthrough in alleviating graft rejection. Here, ER-targetable liposome is prepared via the surface modification of ER-targeting peptide (Pardaxin), which efficiently loads and directly delivers small molecule inhibitor of UPR sensor IRE1α into the ER of lymphocytes, inducing a systemic immunosuppression that facilitates tumorigenesis and metastasis in the tumor inoculation challenge in vivo. And in vitro, a stage-differential dependency of IRE1α in the phase transition of T-8 is identified. Specifically, inhibiting IRE1α at the early responding stages of T-8, especially at the activation phase, results in a shrunk proliferation, impaired effector function, and limited memory commitment, which might contribute centrally to the induced overall immunosuppression. Based on this, a classical acute rejection model, murine full-thickness trunk skin allograft that primary arises from the hyperactivity of T-lymphocyte, is used. Results suggest that lymphocytic IRE1α inactivation attenuates transplant rejection and prolongs graft survival, with a limited effector function and memory commitment of host T-8. Moreover, an even higher immunosuppressive effect is obtained when IRE1α inhibition is used in combination with immunosuppressant tacrolimus (FK506), which might owe to a synergistic regulation of inflammatory transcription factors. These findings provide a deeper insight into the biological polarization and stress response of lymphocytes, which might guide the future development of allogeneic transplantation.

Immune responses to allografts represent a major barrier in organ transplantation. Immune tolerance to avoid chronic immunosuppression is a critical goal in the field, recently achieved in the clinic by combining bone marrow transplantation (BMT) with kidney transplantation following non-myeloablative conditioning. At high levels of chimerism such protocols can permit central deletional tolerance, but with a significant risk of graft-versus-host (GVH) disease (GVHD). By contrast, transient chimerism-based tolerance is devoid of GVHD risk and appears to initially depend on regulatory T cells (Tregs) followed by gradual, presumably peripheral, clonal deletion of donor-reactive T cells. Here we review recent mechanistic insights into tolerance and the development of more robust and safer protocols for tolerance induction that will be guided by innovative immune monitoring tools.

New options to pharmacologically modulate fundamental mechanisms of regulated cell death are rapidly evolving and found first clinical applications in cancer therapy. Here, we present an overview on how the recent advances in the understanding of the biology and pharmacology of cell death might influence research and clinical practice in solid organ transplantation. Of particular interest are the novel opportunities related to organ preservation and immunomodulation, which might contribute to promote organ repair and to develop more selective ways to modulate allogeneic immune responses to prevent rejection and induce immunological tolerance.

T cells play a critical role in immune responses as they specifically recognize peptide/MHC complexes with their T-cell receptors and initiate adaptive immune responses. While T cells are critical for performing appropriate effector functions and maintaining immune memory, they also can cause autoimmunity or neoplasia if misdirected or dysregulated. Thus, T cells must be tightly regulated from their development onward. Maintenance of appropriate T-cell homeostasis is essential to promote protective immunity and limit autoimmunity and neoplasia. This review will focus on the role of cell death in maintenance of T-cell homeostasis and outline novel therapeutic strategies tailored to manipulate cell death to limit T-cell survival (eg, autoimmunity and transplantation) or enhance T-cell survival (eg, vaccination and immune deficiency).

The present review updates the current status of basic, preclinical, and clinical research on donor hematopoietic stem cell infusion for allograft tolerance induction.

Recent basic studies in mice provide evidence of significant involvement of both central deletional and peripheral regulatory mechanisms in induction and maintenance of allograft tolerance effected through a mixed chimerism approach with donor hematopoietic stem cell infusion. The presence of heterologous memory T cells in primates hampers the induction of persistent chimerism. Durable mixed chimerism, however, now has been recently induced in inbred major histocompatibility complex-mismatched swine, resulting in tolerance of vascularized composite tissue allografts. In clinical transplantation, allograft tolerance has been achieved in human leukocyte antigen-mismatched kidney transplantation after the induction of transient mixed chimerism or persistent full donor chimerism.

Tolerance induction in clinical kidney transplantation has been achieved by donor hematopoietic stem cell infusion. Improving the consistency and safety of tolerance induction and extending successful protocols to other organs, and to organs from deceased donors, are critical next steps to bringing tolerance to a wider range of clinical applications.

Although the scarcity of clinical trials with de-novo immunosuppression has been typical over the last 2 years, several attempts have been made in drug conversion, dosing optimization, and bioequivalence. On the basis of recent clinical and animal studies, future directions of management and treatment are outlined.

Studies with new tacrolimus formulations showed better bioavailability and lower doses, which might translate into less toxicity. The long-term results of studies with costimulation blockade confirmed their safety and efficacy. Calcineurin inhibitor (CNI)-free regimens based on mTOR inhibitors were shown to be associated with increased risk of the humoral response. Therefore, ongoing trials are predominantly designed to minimize calcineurin inhibitor dose only. Biologics, such as B-cell-specific agents (bortezomib and rituximab) and complement inhibitors (eculizumab) used to treat antibody-mediated rejection, recurrence of glomerulonephritis, are shifted to more preventive applications. The pretransplant quantification of alloreactive memory/effector T cell response may help to better stratify a patient's immunologic risk and allow for drug minimization.

Despite clinical trials with innovative protocols with already established agents, tacrolimus-based and induction-based protocols have been shown to be the mainstay of immunosuppressive regimens. In the future, research aims to focus on biomarker-driven immunosuppression and cell therapy approaches.

Innovative and exciting advances in the clinical science in solid organ transplantation continuously realize as the results of studies, clinical trials, international conferences, consensus conferences, new technologies and discoveries. This review will address to the full spectrum of news in transplantation, that verified by 2013. The key areas covered are the transplantation activity, with particular regards to the donors, the news for solid organs such as kidney, pancreas, liver, heart and lung, the news in immunosuppressive therapies, the news in the field of tolerance and some of the main complications following transplantation as infections and cancers. The period of time covered by the study starts from the international meetings held in 2012, whose results were published in 2013, up to the 2013 meetings, conferences and consensus published in the first months of 2014. In particular for every organ, the trends in numbers and survival have been reviewed as well as the most relevant problems such as organ preservation, ischemia reperfusion injuries, and rejections with particular regards to the antibody mediated rejection that involves all solid organs. The new drugs and strategies applied in organ transplantation have been divided into new way of using old drugs or strategies and drugs new not yet on the market, but on phase Ito III of clinical studies and trials.