Pathogenesis of a Local Graft versus Host Reaction: Immunogenicity of Circulating Host Leukocytes

Elkins, William L.; Guttmann, Ronald D.

doi:10.1126/science.159.3820.1250

Cited by 88 publications

(20 citation statements)

References 10 publications

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“…This conclusion ostensibly was congruent with the identification of the 'sessile' and/or recirculating passenger leukocytes of BM origin contained in all organs, as the immunogenic component of allografts [28][29][30] . When it was subsequently learned that most of these 'passenger leukocytes' are replaced in the engrafted organ by comparable recipient cells, it was assumed that the donor leukocytes had undergone immune destruction either within the graft or after their migration to host lymphoid organs, with selective preservation of the specialized parenchymal cells of the organ.…”

Section: Clinical Organ Transplantation 1959-1991supporting

confidence: 64%

“…Similarly, allografts lose immunogenicity when their passenger leukocytes are removed from tissues or organs in 'parking experiments' [28][29][30] or by other means. The reduced immunogenicity has been explained by the elimination of leukocyte subsets expressing MHC class II antigens or co-stimulatory molecules, such as B7 (CD80/86) -for example, donor dendritic cells 41 .…”

Section: Immune Ignorancementioning

confidence: 99%

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Transplantation tolerance from a historical perspective

2001

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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

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Section: Clinical Organ Transplantation 1959-1991supporting

confidence: 64%

Section: Immune Ignorancementioning

confidence: 99%

Transplantation tolerance from a historical perspective

2001

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“…Evidence of an intragraft GVH reaction mounted by the graft's passenger leukocytes has been reported in animals 40 and humans. 41 Consistent with such reports, B7 was expressed by donor but almost no recipient cells in the LEW heart allografts of the present study that had been transplanted to BN recipients who were immunologically defenseless because they had been pretolerized with an orthotopic LEW liver (group 6).…”

Section: Discussionmentioning

confidence: 99%

Donor and recipient leukocytes in organ allografts of recipients with variable donor-specific tolerance: With particular reference to chronic rejection

et al. 2000

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We have attributed organ engraftment to clonal exhaustion-deletion of host-versus-graft and graft-versus-host reactions that are reciprocally induced and governed by migratory donor and recipient leukocytes. The so-called donor passenger leukocytes that migrate from the allograft into the recipients have been thoroughly studied (chimerism), but not the donor leukocytes that remain in, or return to, the transplanted organ. Therefore, using flow cytometry we determined the percentage and lineages of donor leukocytes in cell suspensions prepared from Lewis (LEW) cardiac allografts to 100 days posttransplantation. The LEW hearts were transplanted to naïve untreated Brown Norway (BN) recipients (group 2), to naïve BN recipients treated with a 28-day or continuous course of tacrolimus (TAC) (groups 3 and 4), and to drug-free BN recipients pretolerized by earlier bone marrow cell (BMC) or orthotopic LEW liver transplantation (groups 5 and 6). The findings in the heart cell suspensions were correlated with the results from parallel histopathologic-immunocytochemical studies and other studies of the grafts and of host tissues. Although the LEW heart allografts were rejected in 9.6 days by the unmodified recipients of group 2, all beat for 100 days in the recipients of groups 3 through 6. Nevertheless, all of the long-surviving cardiac allografts (but not the isografts in group 1) were the targets of an immune reaction at 5 days, reflected by dramatic increases in the ratio of leukocytes to nonleukocyte nucleated cells from normal values of 1:5-1:6 to 1:1-5:1 and by manifold other evidence of a major inflammatory event. The acute changes returned to baseline by 100 days in the chronic rejection (CR) free hearts of groups 4 and 6, but not in the CR-afflicted hearts of short-course TAC group 3 or the less-severely damaged hearts of the BMC-prime group 5.The freedom from CR in groups 4 and 6 was associated with a large donor contribution to the intracardiac leukocyte population at 5 days (28.6% and 22% in the respective groups) and at 100 days (30.5% in group 4 and 8.4% in group 6) compared with 2% and 1.2% at 100 days in the CR-blighted allografts of the partially tolerant animals of groups 3 and 5. Whether large or small, the donor leukocyte fraction always included a subset of class II leukocytes that had histopathologic features of dendritic cells. These class II ؉ cells were of mixed myeloid (CD11-b/c ؉ ) and lymphoid lineages; their migration was markedly inhibited by TAC and accelerated by donor-specific priming and TAC discontinuance. Although a large donor leukocyte population and a normal leukocyte/nonleukocyte cell ratio were associated with freedom from CR, these findings and the lineage profile of the intracardiac leukocytes were not associated with tolerance in the animals of groups 3 and 4 under active TAC treatment. The findings in this study, singly and in their entirety, are compatible with our previously proposed leukocyte migration-localization paradigm of organ allograft acceptance and tolerance. (Liver ...

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“…However, tolerance is not induced, as shown by the fact that rejection can be readily precipitated with an injection of donor leukocytes. 41 Secondary. Pristine examples of immune indifference are not seen in the usual setting of clinical organ transplantation.…”

Section: Clonal Exhaustion/deletionmentioning

confidence: 99%