Current advances and remaining challenges in human transplant immunology

A variety of solid organs, tissues and cell types are currently used for human transplantation and are the therapy of choice in an increasing number of clinical situations. Transplants are being performed in order to prolong life, improve or restore health and enhance the quality of life. Based on Organ Procurement and Transplantation Network data, 28 954 life-saving solid organ transplants including kidney, heart, liver, pancreas, bowel and lung were completed in 2013 with an astonishingly excellent success rate (http://optn.transplant.hrsa.gov). Over 13 500 allogeneic bone marrow transplants were carried out last year transforming lethal hematological diseases into curable illnesses (www.marrow.org). In the United States, over 42 000 corneal transplants were completed in 2009 improving or restoring sight to visually impaired individuals (http://www.restoresight.org/). In the future, induced pleuripotent stem cell transplants hold an almost limitless promise to treat human illnesses such as autoimmune diabetes, Parkinson’s disease and spinal injury just to name just a few (Inoue et al., 2014).

The remarkable advances in clinical transplantation have been made possible through basic research efforts. Initially, drug discoveries such as cyclosporin and sirolimus led to a better understanding of signaling pathways required for immune activation and transplant rejection. Exploiting this knowledge, modern scientific technologies are now uncovering novel immunoregulatory pathways, designing highly specific biological immunotherapies and applying comprehensive genetic analysis to better understand and manipulate rather than suppress alloimmune response. Yet, significant challenges persist that continue to defy attempts to create specific tolerance to transplanted tissue without inducing global immunosuppression. It is with this background that we present the current issue of Immunological Investigations focusing on new concepts in the basic and clinical sciences of transplantation.

Ever since the first kidney transplant was made possible between identical twins, it was clear that the major barrier to successful solid organ transplantation resides in the disparity between donor and recipient Human Leukocyte Antigens (HLA). Today’s organ matching techniques rely on high resolution HLA typing performed by combining PCR DNA amplification with flow cytometry. In this issue, Rey et al. demonstrate, using high resolution HLA typing, that previously unsuspected differences and similarities exist amongst indigenous populations (Rey et al., 2014). These findings are generally applicable to the study of population dynamics, disease susceptibilities, pharmacogenomics as well as defining optimal organ allocation paradigms.

McGuire et al. describe the most recent advances and applications of flow cytometry in transplantation (Maguire et al., 2014). Technical innovations in flow cytometry now provide clinicians and scientists a more discerning approach towards identifying and monitoring potential immunological risks in both pre-transplant and post-transplant settings. In addition, advances in the ability of flow cytometry to identify low frequency but meaningful subsets of immune cells along with the power to study intracellular signaling events offers new possibilities to study and manipulate the immune system towards tolerance. The paper by Pankewycz et al. reviews the latest developments in understanding the importance of alloantibody responses in renal transplantation (Pankewycz et al., 2014). Their review describes the critical role of alloantibodies in all phases of renal transplantation from organ allocation and matching to rejection and graft failure. The difficult therapeutic challenges posed by the appearance of alloantibodies, the possible mechanisms underlying their development and future directions in blocking allosensitization are also discussed.

The following three papers review new developments in clinical immunosuppressive therapy used during different phases of the transplant process. Laftavi et al. (2014) describe the various approaches to induction therapy given at the time of implantation that differ according to the individual patient’s immune risk profile. The authors detail the immunological effects of the diverse induction therapies available, their lasting biological effects and impact on long-term graft survival as well as their influence on maintenance drug therapy.

The papers by Brar & Nader (2014) and Solliman et al. describe the immunological risks and benefits of different maintenance immunosuppressive strategies which begin simultaneously with or after induction therapy and continue for the lifetime of the graft (Brar & Nader, 2014; Soliman et al., 2014). The paper by Brar and Nader reviews the clinical trials that attempt to reduce maintenance immunosuppressive drug therapy following renal transplantation. Immunosuppressive drug minimization remains a useful goal in order to avoid the toxicities and immune compromise caused by these potent agents. However, the initial successes observed with drug avoidance/minimization therapies it is not a reliable estimate of tolerance or lack of responsiveness in the recipient since the effects of this strategy may not become evident for years.

The paper by Soliman et al. describes a different approach to minimizing long-term drug toxicities and improving graft survival by switching drug therapy towards a more innocuous and perhaps toleragenic combination. Unfortunately, their attempt to reduce exposure to calcineurin inhibitors, known nephrotoxins, by changing therapy to an mTOR inhibitor, sirolimus, failed to improve graft survival or function over a period of 10 years. These results demonstrate our continued dependence on chronic drug therapy and the critical need for rationally designed and more specific biological agents.

Towards this end, the following two papers highlight some of the newer concepts in basic transplantation immunology. The review by Ebrahimi & Rahim (2014) describes various experimental methods to achieve transplant success by manipulating rather than suppressing the immune response. These authors describe several experimental approaches in immunotherapy such as the development of infusion therapy using toleragenic cells or their components, physical barriers to allorecognition as well as extracorporeal means of immunomodulation.

Several of these modalities show promise in preclinical models of transplantation. Recent evidence also supports the concept that CD4 + CD25 + FoxP3+ T regulatory cells may be useful and perhaps specific tools to induce transplant tolerance (Edozie et al., 2014). In an original research paper by Hu et al. (2014), the authors describe that increased levels of CD4 + FoxP3 + T cells lacking CD25 surface expression (CD4 + CD25-FoxP3+) correlate with acute graft rejection and poor outcomes. This study emphasizes the complexity and plasticity of regulatory lymphocyte populations that continue to defy their clinical application.

Allogeneic stem cell transplantation (SCT) presents a different immunological challenge compared to solid organ transplantation. SCT may result either in host versus graft disease or graft versus host disease (GVHD) leading to graft failure or organ damage respectively. The paper by Manjili & Toor (2014) calls into question whether the clinical manifestations of GVHD are solely due to alloreactivity. Rather, the authors focus on the contribution of tissue damage caused by intensive preconditioning regimens to GVHD. They detail evidence that preconditioning leads to a breakdown of normal homeostatic repair processes and impairs local immunity in areas exposed to environmental pathogens. This process creates the ideal circumstances for T cell activation that may account for the site-specific manifestations of GVHD. Focusing on efforts to limit tissue damage and improve repair mechanisms may lead to less vigorous GVHD and improve patient survival. The immunological basis of SCT is ably reviewed in the paper by Mosaad (Mosaad, 2014). The author discusses the goal of creating a genetically engineered universal donor stem cell line having universal applications.

The final article in this compilation is the extensive and thorough review of corneal transplantation by Kumar & Kumar (2014). Corneal transplantation is the oldest form of solid tissue transplantation and remains the most commonly performed transplant procedure worldwide. The authors describe the many unique immune features of the eye normally considered to be an immunologically privileged site. Yet, rejection remains a considerable challenge to corneal engraftment. The process of corneal transplantation, the anatomy of the eye and the immune processes of rejection unique to this remarkable organ are all described in this well-written review.