Transplantation tolerance from a historical perspective

Abstract

Although transplantation immunology as a distinctive field began with the development of experimental models that showed the feasibility of bone marrow transplantation, organ engraftment was accomplished first in humans, and was thought for many years to occur by drastically different mechanisms. Here, we present our view of the concepts of allograft acceptance and acquired tolerance from a historical perspective, and attempt to amalgamate them into simple and unifying rules that might guide improvements in clinical therapy.Our paradigm of transplantation immunology (reviewed in Ref. 1) had its origin in the nineteenth century. After the cellular, humoral and complement constituents of the immune response were discovered (see Timeline), evidence emerged that an immune reaction was responsible for the failure of transplanted tissue and most tumour allografts to survive indefinitely 2 . When transplantation research declined during and after the First World War, these early accomplishments faded. Similarly, the significance of the Neonatal tolerance shown in tumour and viral-infection models was not fully appreciated until Burnet's formulation of the tolerance and Clonal-Selection hypothesis 3 . Finally, the phenomenon of Immune ignorance was first shown in 1934 (Ref. 4), but discounted until its rediscovery many years later 5,6 . The immunological basis of rejectionModern transplantation immunology is often dated to the experiments by Medawar in 1944, which showed that skin allograft rejection is a Host-versus-graft (HVG) response 7 , the cellmediated features of which were later defined by Mitchison 8 . The term major histocompatibility complex (MHC) was introduced by Gorer, Lyman and Snell 9 for the genetic locus that encodes antigens associated with allograft rejection, tumour surveillance and other expressions of cell-mediated immunity. The MHC-restricted mechanisms of T-cell

Tolerance for organ recipients: A clash of paradigms

“…14,15,17,18 It follows that the completeness of tolerance short of the drug-free state can be inferred from the amount of immunosuppression needed to maintain graft stability. 18,24,25 None of the patients of Donckier et al 1 had macrochimerism. But the first 2 recipients clearly achieved a high degree of drug-free tolerance that can be considered with certainty to be microchimerism dependent.…”

“…25 Such heavy treatment also would be expected to abrogate the potential benefit of additional infused cells. When over-immunosuppression is later reduced, recovery of the inefficiently deleted clone would leave the patient prone to chronic rejection and dependent on lifetime drug treatment.…”

“…25 Ratcheting down the response arm with immunosuppression as shown in Figure 1A has been the usual means of perpetuating organ alloengraftment, but at the costly loss of T-cell surveillance of malignant neoplasms and infections. The less damaging possibility of tilting the balance by simply giving organ recipients adjunct donor leukocyte infusions has been shown empirically to improve allograft survival in numerous experimental transplant models.…”

Non‐myeloablative mixed chimerism approaches and tolerance, a split decision

“…In hindsight this may not be surprising given that tolerance naturally occurs primarily in the thymus and only secondarily in the periphery [2]. In contrast, the approach of generating hematopoietic chimerism via bone marrow transplantation (BMT) takes advantage of the thymic central tolerance mechanisms, and is considered the most robust method of inducing donor-specific tolerance [3][4][5][6]. The chimer- ism approach is limited clinically by the harsh recipient conditioning needed to establish chimerism and the possibility of graft-vs.-host disease [7].…”

Achieving Donor-Specific Hyporesponsiveness Is Associated with FOXP3+ Regulatory T Cell Recruitment in Human Renal Allograft Infiltrates

“…In the clinical setting, tolerance or "prope" tolerance has been defined as evidence of donor-specific un/hyporesponsiveness with recovered third party response in functional in vitro assays, lack of circulating donor-specific alloantibodies and absence of destructive lymphocyte infiltration in allograft biopsies in patients without or with minimal amount of immunosuppression. In fact, in clinical transplantation, the main therapeutic approach for reaching a tolerogenic state has been based on two sequential steps: first, recipient T cell depletion and then, the use of minimal posttransplant immunosuppression (13). Actually, such strategy has been performed in kidney (14 -16) and liver (17) transplantation using tacrolimus (TAC) or sirolimus (SRL) as maintenance immunosuppressive drugs.…”