Surgical Milestones
Vascular surgery, preceding solid organ transplantation, did not emerge as a specialty until the end of the 19th century. Prior to this, its history was marred by extremely high rates of failure in sporadic efforts by daring individuals. In 1897, John B. Murphy performed the first clinical end-to-end suture of an artery [3] . His technique consisted of invaginating the severed ends of the artery, then inserting the proximal end into the lumen of the distal end, suturing all this together. Experiments in arterial suturing continued without success for another few years, but were doomed to failure because of the major complications of disruption, infection, and local thrombosis. It was not until Alexis Carrel introduced a "leak-proof" technique for anastomosing blood vessels without constricting the lumen or causing thrombosis. Anastomosing blood vessels was a crucial element required to progress the field of solid organ transplantation. Carrel demonstrated the feasibility of grafting veins to arteries, and arteries to arteries using his innovative anastomotic approach [4, 5, 6] . In conjunction with Morel, he was able to successfully transplant the kidney of a dog from its normal location to the neck by suturing the renal artery and vein to the dog's common carotid artery and external jugular vein, respectively [4] . Carrel was unsuccessful in passing the clinical examinations for a surgical position on the faculty at Lyons, and left France to pursue his career in French Canada. After presenting a paper on vascular anastomosis at an international congress, he was recruited by Karl Beck to the University of Chicago, where he worked with Charles Guthrie in the Hull physiological laboratory. Their work detailed the refinement and perfection of vascular anastomotic techniques, the usage of vein grafts in the arterial system, the development of tissue preservation techniques, and organ and limb transplantation [6, 7, 8] . Alexis Carrel performed the first heterotopic canine heart transplant with Charles Guthrie in 1905 [6] . At the time, he clearly recognized the difference in the survival times between autografts and allografts in experimental animals, but he did not conceptualize rejection as distinct from other graft-destroying processes. Twenty years later, the concept of cardiac allograft rejection was proposed by Frank Mann at the Mayo Clinic to explain the eventual failure of heterotopic canine allografts. He described the rejection process as a "biologic incompatibility between donor and recipient" manifested by an impressive leukocytic infiltration of the rejecting myocardium [9] .

Understanding Allo-Immunity
In 1901, Karl Landsteiner, working as an assistant in the Institute of Pathological Anatomy at the University of Vienna, published a paper demonstrating that clumping of the donor's red blood cells was responsible for the clinical manifestations of the transfusion reaction [10] . This paper revealed that the clumping was due to the presence of iso-agglutinins in the recipient's serum. He described 3 different types of iso-agglutinins, which formed the basis for his blood group classification known initially as A, B, and C. His suggestions received little attention until 1909, when he classified the human blood into the A, B, AB, and O groups and showed that catastrophic reactions can occur when a person receives blood from a different group [10] . Compatibility was later found to be not only a requirement for transfusion, but for transplantation.

Peter Medawar was the first to demonstrate that the immune system was responsible for the rejection of transplanted organs, and later went on to show that it could be "tricked" into tolerating transplanted tissues. Medawar started his pioneering work in Glasgow on skin grafting burns. He found that skin grafted from a donor lasted about 10 days, but a second graft was rejected immediately. It was as though the immune system remembered what the intruder looked like, and promptly rejected it [11] . The host fought the transplant as it would a foreign pathogen. Medawar suggested that the rejection was an immunological process. Later, while experimenting with skin grafts in twin cattle, Medawar thought that non-identical twin cattle, different sexes, for instance, would reject grafts from their other half. To his surprise he found that was not so and that all twins, identical or fraternal, accepted the grafts. He postulated that something happened to the cattle immune system while they were still in utero so they could accept and tolerate each other's tissue [12, 13] .

In the early 1950's, Medawar inoculated mouse embryos with the cells of mice from another strain. After their birth they were grafted with skin taken from the strain of mice to which they had been exposed in utero. Theoretically they should have been rejected, but they weren't. They had, as he put it, an acquired immunological tolerance [14] . Medawar thought all this very interesting, but of little practical value, but 30 years later wrote "The ultimate impact of the discovery of tolerance turned out to be not practical but moral; it put new heart into biologists and surgeons who were working to make it possible to graft kidneys from one person to another." [15]

Frank Burnet of the University of Melbourne in Australia suggested that the body's immune cells learn very early on to accept whatever tissues are there as part of the body and only attack and reject material that shows up later. This theory later developed the notion of clonal selection and the recognition of self and non-self by vertebrate immune systems [16] . In 1958, French physician Jean Dausset described the first leukocyte antigen, MAC (now known as HLA-A2) [17, 18] . The discovery allowed for tissue matching beyond blood types.

Successful Organ Transplants
The first (unsuccessful) renal transplant from a deceased donor was carried out by the Ukrainian surgeon Yu Yu Voronoy in 1933, the first human renal transplant with long-term survival of the graft was performed on identical twins in 1953 by Joseph Murray at the Peter Bent Brigham Hospital in Boston, Massachusetts [19, 20] . In 1964, the first heart transplant of a non-human primate into a human was performed by James Hardy of the University of Mississippi. The heart of a chimpanzee was transplanted into the 68-year old Boyd Rush; however, the heart was too small to maintain independent circulation and functioned only for 90 minutes before failing [21] . Christiaan Barnard successfully transplanted the heart of Denise Darvell, a young woman who had died in a car crash, into 53-year-old Louis Washkansky. He died of pneumonia 18 days later [22] . In 1969, Denton Cooley implanted the first total artificial heart (the Liotta Total Artificial Heart) at the Texas Heart Institute in Houston. The heart was implanted into the 47-year old Haskell Karp, but was not intended to be permanent. It was used as a bridge to transplant until he could receive a donor heart, which he did 64 hours later [23] .

Immunosuppressive Drug Discovery
In 1962, Imuran® (azathioprine) was discovered by Gertrude Elion and George Hitchings. It was one of the first agents able to block the body's rejection of foreign tissues [24] .

Cyclosporine was discovered in 1971 by Jean-Francois Borel from a metabolic of the fungus Beauveria nivea [25] . It was the first immunosuppressive agent which allowed selective immunoregulation of T-lymphocytes without excessive toxicity. Cyclosporine suppresses the immune system by inhibiting the signal transduction pathway responsible for the activation of B-lymphocytes and T-lymphocytes. Briefly, cyclosporine binds to cyclophilin, producing an intracytoplasmic cyclosporine/cyclophilin complex [26] . This complex acts as a composite surface and blocks the phosphatase activity of calcineurin [27] . Calcineurin is a calmodulin-dependent serine/threonine phosphatase and a key participant in T-lymphocyte activation. Inhibition of calcineurin prevents dephosphorylation of nuclear factor of activated T-lymphocytes (NFAT) and leads to the blockade of translocation of NFAT to the nucleus. NFAT is expressed mainly in leukocytes, where it plays a key role in the regulation of a large number of inducible genes during immune activation such as interleukin-2 (IL-2) and CD40 ligand [28] . There is also evidence that cyclosporine participates in the expansion of T-suppressor populations [29] and may also disrupt lymphokine-dependent T-lymphocyte-macrophage interactions [30] .

Cyclosporine was approved for clinical use in transplantation by the United States Food and Drug Administration (US FDA) in 1983, and since then, has revolutionized the management of post-transplant rejection. Cyclosporine has been shown to improve one year patient survival rates in cardiac transplant recipients; however, has not significantly impacted long-term survival rates or incidence of cardiac allograft vasculopathy [31, 32, 33] . Human and animal studies have demonstrated that cyclosporine may, in fact, have a significant effect on the development and progression of coronary intimal thickening in heart transplant recipients in whom calcineurin inhibition is incomplete [34, 35] .

Development of mycophenolate mofetil (MMF), an inosine 5'-monophosphate dehydrogenase (IMPDH) inhibitor, began in 1982, and research continues on other IMPDH inhibitors. MMF is an ester pro-drug that is hydrolyzed to the active immune suppressor mycophenolic acid (MPA). MPA inhibits the activity of IMPDH, a key enzyme in the de novo pathway of guanosine nucleotide synthesis in B- and T-lymphocytes that slows their proliferative response. The unique property of MMF is its lack of atherogenic and chronic nephrotoxic adverse effects [36] .

In 1984, a substance was discovered in a soil sample taken at the foot of Mt. Tsukuba which stands just outside Tokyo. The substance, given the name tacrolimus, was found to possess a powerful suppressive effect on IL-2 production. Based on evidence that tacrolimus was able to block initial T-lymphocyte activation, inhibiting the differentiation and proliferation of cytotoxic T-lymphocytes, speculation about the substance's immunosuppressive properties grew. The mechanisms of its immunosuppressive properties are very similar to cyclosporine, but it is 10 to 100 times more potent on a per gram basis [37, 38] .

Interest in the antibiotic sirolimus (Rapamycin®), a product of Streptomyces hygroscopicus, was renewed in the 1980s when it was shown to prevent allograft rejection. Sirolimus and tacrolimus are related structurally and compete for the same intracellular protein, forkhead binding protein-12 (FKBP12). In 2000, it was demonstrated that sirolimus works late in the cell cycle (G1) by inhibiting the regulatory kinase mammalian target of RAPA (mTOR) involved in signal transduction of T cell growth factors such as IL-2 and of the co-stimulating molecule CD 28 [39, 40, 41] . Use of sirolimus has improved graft survival rates and decreased rejection incidence and severity [39, 40] . Sirolimus has been shown to be effective when used in combination with cyclosporine [42] . Sirolimus use has also permitted cyclosporine target-level reduction, thereby avoiding or minimizing nephrotoxicity secondary to calcineurin inhibitors. This is because the sirolimus-FKBP12 complex does not inhibit IL-2 production, unlike the tacrolimus-FKBP12 complex [40] . In 1999, the US FDA recommended the approval of Rapamune® (sirolimus) in the use of prevention of organ rejection. Everolimus is a derivative of sirolimus and has been shown to have similar mechanisms of action [43, 44] .

Pathological Diagnosis
The detection of allograft rejection is one of the most important yet ill-defined areas of cardiac transplantation. The investigation of the transvascular endomyocardial bioptome by Sakakibara and Konno in 1963 [45] , and the introduction of transvenous endomyocardial biopsy by Philip Caves in 1973 finally provided a reliable means for monitoring allograft rejection [46] . Throughout the 1980's, various scales emerged from different centers, causing much confusion. The International Society of Heart and Lung Transplantation (ISHLT) commissioned the development of a common grading scale in 1990, in an attempt to develop uniform description and grading criteria of various transplant histologies to refine communication and comparison of treatment regimens and outcomes between transplant centers. Due to the hard work and diligence of cardiac pathologists such as Margaret Billingham, the ISHLT grading system for cellular rejection was developed in 1990 [47] . In 1996, a group of leading transplant pathologists attempted, unsuccessfully, to further revise these criteria. In 2004, a further review of the grading scale was commissioned by the ISHLT to address the challenges and inconsistencies in the use of the old grading system [48] . Because the 1990 grading system has allowed for better consistency in assessment of rejection severity, there are inherent limitations to its usage: there remains variability in assessment of rejection severity, particularly regarding grade 2 lesions and the presence of Quilty lesions (endocardial infiltrates). Confusion regarding these two entities tends to cause overestimation of rejection severity. In addition humoral rejection had not been addressed.

With advances in immunosuppression and surgical techniques, the pathologies seen post-transplantation have followed suit. Over the last 20 years, the rates of acute rejection and infection leading to graft failure have greatly declined owing to refined immunosuppressive drug regimens, better diagnosis of ischemic injury, and improved monitoring of immune status. As such, chronic rejection and cardiac allograft vasculopathy have become more prominent issues in transplantation medicine. Cardiac allograft vasculopathy is an accelerated form of atherosclerosis which occurs visibly in about 30-60% of transplant recipients within the first 5 years post-transplantation [49] . Studies using intravascular coronary ultrasound techniques have demonstrated intimal thickening in 75% of cardiac allograft recipients by the end of the first year post-transplantation [50] .

A hemodynamic change in the absence of acute cellular rejection is termed biopsy-negative rejection, and occurs in 10 to 20% of cardiac allograft recipients [51] . In the pre-cyclosporine era, biopsy-negative rejection was not apparently an important or common phenomenon. However, it has long been suggested that immunologic pathways other than lymphocytic infiltration are important in mediating cardiac allograft dysfunction and injury, and humoral rejection may be the primary mediator [52, 53] . Humoral rejection is associated with increased graft loss, accelerated coronary allograft vasculopathy, and increased mortality [52, 53] .

Emerging Horizons
Many new horizons exist for further improvement in the field of heart transplantation, including increasing donor availability, developing new approaches to prevention or interdiction on failing hearts, furthering our understanding of acute and chronic rejection, and movement towards personalized and predictive molecular medicine.

Although there have been major advancements in the prevention and treatment of advanced heart failure, including the use of lipid-lowering drugs (HMG CoA reductase inhibitors), angiotensin-converting enzyme inhibitors, β-blockers, and aldosterone antagonists, there remains a discrepancy between the number of donor organs available and the number of patients on the wait list for cardiac transplantation. Many efforts have been made to increase the donor pool by altering criteria for transplantation or by increasing organ donation. Despite these strategies, even if all potential organ donations were obtained, there would still be inadequate numbers to satisfy current and future demands [54] . As such, it is also important to focus future efforts on furthering the prevention and treatment of heart disease.

The use of mechanical assist devices as a bridge or temporary alternative to transplantation can be a life-saving procedure in patients with advanced heart failure and are awaiting transplantation. It has been shown that transplantation of patients who receive mechanical assist devices result in survival rates comparable to those with conventional transplantation [55, 56] , and that the survival benefit for these patients is better than for non-supported patients. For some patients who do not meet the criteria for transplantation, mechanical assist devices may be considered as destination therapy [57] .

The utilization of new non-invasive techniques to monitor the development of coronary allograft vasculopathy will also help to provide proper control of the immune status of the transplant recipient. Intravascular ultrasound (IVUS) and Doppler flow have been used to demonstrate the presence of vascular lesions within transplanted organs [58, 59, 60] , but there is great need for simple and accurate markers of immune status to minimize care, prevent graft failure, minimize toxicity, and reduce costs. Several groups have initiated molecular (genomic and proteomic) studies in attempts to identify potential biomarkers for the prediction of acute and chronic rejection in solid organ allografts [61, 62, 63, 64, 65, 66] . With the advent of microarray technologies in recent years, many groups have profiled biopsy or serum samples attempting to identify potential markers of rejection. Sarwal et al. conducted systematic analysis of gene expression patterns from biopsy samples from patients with acute renal allograft rejection [67] . They demonstrate that patients indistinguishable on histological analysis reveal extensive differences in gene expression, which are associated with differences in immunologic and cellular features and clinical course. The findings of Sarwal et al. indicate that acute rejection is heterogeneous at the molecular level, even when findings using conventional light microscopy are similar [67] . For example, even though CD8 and CD4 T-lymphocytes were prominent upon light microscopic examination in patients with acute rejection, the levels of expression of T-lymphocyte-specific and T-lymphocyte-inducible genes differed among biopsy specimens. These findings re-enforce the idea that the mere presence of resident or trafficking T lymphocytes in tissues does not reflect their function. It may be suggested that some infiltrating T-lymphocytes may be related to the induction of tolerance or long-term graft acceptance without the need for continued immunosuppression [68] .

In a study by Marboe et al., the peripheral blood molecular profile of acute rejection and Quilty lesion formation was compared using a clinically validated multi-gene PCR test for acute rejection performed on peripheral blood and used to complement diagnosis by intramyocardial biopsy. Cases with discrepancies between local pathologist diagnosis of Grade 2 or 3A and cardiac pathologist-rendered diagnosis of Grade 0-1 with Quilty lesions exhibited clear separation into rejection and quiescent profiles upon gene expression analysis. This study demonstrates that molecular testing provides a means to identify immunologic quiescence in uncertain cases and may help to reduce errors resulting from the current ISHLT classification system [69] .

Thomas Starzl, in recognition of the insights of Peter Medawar, proposed that "transplant recipients do not have to take a lifetime regimen of potentially dangerous anti-rejection medicine", and that allograft tolerance could ideally be induced in the recipient such that the tissue would be accepted as self by the host's immune system [70, 71, 72, 73] . His pioneering work in transplantation, starting at the University of Colorado, came to maturation during his tenure at the University of Pittsburgh. He made many extraordinary contributions to transplantation medicine and science: he established the clinical utility of cyclosporine in 1982, and tacrolimus in 1991, both leading to FDA approval; he developed multiple technical advances in organ preservation, procurement and transplantation; he delineated the indications and limitations of abdominal organ transplantation; he defined the underlying basis for organ transplantation as a treatment of inherited metabolic diseases (thus providing the rationale for current-day gene therapy efforts); he recognized the causative role of immunosuppression in the development of post-transplant lymphoproliferative disease and other opportunistic infections and the utility of reversing the immunosuppressed state as the principle treatment; and he proposed the paradigm of microchimerism in organ transplant tolerance.

Current Search for Relative or Absolute Immune Tolerance
There are three steps to achieving transplant tolerance: gradual reduction to low-dose immunosuppression, with non-depleting induction, low-dose maintenance immunosuppression, and steroid free or early steroid withdrawal; minimal immunosuppressive therapy, with depletion of induction and low-dose or single agent maintenance therapy; and tolerance, with clonal B-lymphocyte or T-lymphocyte deletion, co-stimulatory blockade, bone marrow infusion/transplantation, negative signaling, or induction of apoptosis. The challenge still remains to move patients along the continuum from lower dose immunosuppression to the possibility of tolerance.

Closing Comment
In summary, there have been great advances in the last 20 years in the field of transplantation. Improvements in our understanding of transplant rejection and new immunosuppressive therapies to prevent and/or treat rejection will continue to warrant re-examination of future grading systems to provide the transplant community with the most useful and accurate grading criteria. In the future, these grading tools may include molecular biomarkers from plasma, urine, or biopsy tissue to complement the durable standard of intramyocardial biopsies for acute rejection and vascular imaging for chronic rejection.

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