The lost chord: microchimerism and allograft survival

Abstract

Recent evidence suggests that passenger leukocytes migrate after organ transplantation and produce persistent chimerism, which is essential for sustained survival of the allografts. Here, Thomas Starzl and colleagues argure that this hematolymphopoietic chimerism provides an important framework for the interpretation of basic and therapeutically oriented transplantataion research.Medawar's characterization of rejection 1 as a host-versus-graft (HVG) reaction (Fig. 1a) was the cornerstone of transplantation immunology. A decade later, this concept was transposed in the context of a graft-versus-host (GVH) reaction (Fig. 1b), in which histoincompatible hematolymphopoietic grafts rejected the immunologically defenseless recipients 2,3 . The resulting assumption that allograft acceptance or rejection could be understood by studying HVG or GVH immunologic responses in isolation led to prompt acceptance of the one-way in vitro tests of immune reactivity as 'minitransplant' surrogates. However, this assumption did not provide a blanket explanation for observations made in animal and human allograft recipients. The one-way paradigmUntil 1959, preparatory donor leukocyte infusion into cytoablated organ recipients was an expected natural extension of the neonatal tolerance model of Billingham, Brent and Medawar 4 and its adult cytoablation analogues 3 . However, when long-term survival of human kidney allografts was accomplished in a few sublethally irradiated recipients without donor leukocyte infusion, and then regularly without cytoreduction under continuous pharmacologic immunosuppression, the need either for chimerism or host preconditioning lost favor.The identification of 'passenger leukocytes' as the primary antigenic component of organs 6,7 led to the belief that their destruction by the host immune system was essential for organ engraftment. When these cells were found to be migratory 8 , including dendritic cells (DCs) 9 , their sensitization effects and presumed elimination at peripheral and intragraft sites was taken for granted. Bone marrow transplantationMajor histocompatibility complex (MHC)-restricted models of acquired tolerance were widely considered to have validated Burnet's prediction that developing lymphocytes could be purged of self-reactive cells before they achieved functional maturity, even following bone marrow transplantation. The alternative possibility that donor and recipient immunecell populations coexisted in neonatally tolerant animals in a mutually nonreactive state while retaining the ability to function collaboratively (e.g. in a joint immune response to infection) was abandoned when no direct experimental support could be found 10 it has since been learned that the outcome in the neonatal tolerance model is highly variable and that a state approaching permanent clonal deletion is uncommon 11 . Recently, it has been shown that the ability of donor-derived leukocyte subsets to proliferate in response to a skin graft challenge was a more critical determinant of neonatal tole...

Bone Marrow Augmentation in Renal Transplant Recipients

“…40 If so, all the lessons currently being learned with the infusion techniques, including appropriate timing, should be applicable to the pharmacological approach to enhancement of chimerism. 34,37 …”

“…Recipient hematolymphopoietic cytoreduction or cytoablation unquestionably enhances the ease and extent of donor leukocyte engraftment, but the potential penalty with each further increment in cytoreduction is proportionate weakening of the biologic safety device (against GVHD and rejection) that is provided by the nullification effect of the dual cell populations, 34 as has been learned with conventional bone marrow allotransplantation.…”

Microchimerism, Donor Dendritic Cells, and Alloimmune Reactivity in Recipients of Flt3 Ligand-Mobilized Hemopoietic Cells: Modulation by Tacrolimus

“…T he naturally occurring persistence of donor hemopoietic cells in lymphoid and nonlymphoid tissues of organ allograft recipients (microchimerism) (1) is an intriguing immunologic phenomenon that is not well understood and has been the subject of recent debate (2)(3)(4). Whether microchimerism represents a contributory factor toward or a consequence of unresponsiveness to donor alloantigens has not been fully resolved.…”

The Saga of Liver Replacement, with Particular Reference to the Reciprocal Influence of Liver and Kidney Transplantation (1955–1967)

“…In 1995, 12 of our 42 patients (28%) surviving from this era already had been off all immunosuppression for 1 to 17 years. 90 Since then, many of the remaining 30, who are now out to 33 years post-transplantation, also have stopped drugs and remain welJ.9 1 ,92 Such drug-free tolerance was almost unheard of with the other kinds of cadaveric organs.…”