Transplantation Milestones

Starzl, Thomas E.

doi:10.1001/jama.1995.03520350058029

Cited by 32 publications

(6 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…via veto/ suppressor cells, cytokine profile changes or enhancing antibodies. Furthermore, it has been argued that the microchimerism associated with successful transplantation, and conversely its disappearance with or just after irreversible rejection in experimental models 18,20 , is epiphenomenal 24 .In a reassessment based on the discovery of microchimerism in organ recipients, we suggested that the donor leukocytes in organ recipients were components of antagonistic but reciprocally attenuated or abrogated HVG and GVH arms 14,15,21 . Deletion of the host arm by cytoablation prior to bone marrow but not organ transplantation altered the balance in this mutual antagonism and was thus responsible for the disparities in the two different kinds of transplantation (Table 1).…”

mentioning

confidence: 84%

“…1c) 15 both the allograft and recipient become genetic composites. A mirror image condition exists after bone marrow transplantation 21 (Fig. 1d), proved by demonstrating a trace residual population of host leukocytes in essentially all stable, human bone marrow recipients who previously were thought to have complete donor-cell chimerism 22 .…”

Section: The Two-way Paradigmmentioning

confidence: 96%

“…In a reassessment based on the discovery of microchimerism in organ recipients, we suggested that the donor leukocytes in organ recipients were components of antagonistic but reciprocally attenuated or abrogated HVG and GVH arms 14,15,21 . Deletion of the host arm by cytoablation prior to bone marrow but not organ transplantation altered the balance in this mutual antagonism and was thus responsible for the disparities in the two different kinds of transplantation (Table 1).…”

Section: Cause or Effect?mentioning

confidence: 99%

“…The dynamic 'nullification' effect of the two arms explained (1) the poor prognostic value of HLA matching for organ transplantation; (2) the rarity of GVH disease (GVHD) following the engraftment of immunologically active organs, such as the intestine and liver 14,15,21 , and (3) the characteristic cycle of immunologic crisis and resolution, first observed in kidney recipients 25 , that was most-practically monitored by serial changes in organ allograft function (Fig. 2).…”

Section: Cause or Effect?mentioning

confidence: 99%

See 3 more Smart Citations

The lost chord: microchimerism and allograft survival

et al. 1996

View full text Add to dashboard Cite

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...

show abstract

mentioning

confidence: 84%

Section: The Two-way Paradigmmentioning

confidence: 96%

Section: Cause or Effect?mentioning

confidence: 99%

Section: Cause or Effect?mentioning

confidence: 99%

See 2 more Smart Citations

The lost chord: microchimerism and allograft survival

et al. 1996

View full text Add to dashboard Cite

show abstract

“…1,2 In that model, Brown-Norway (BN) rats are pretreated with a Lewis (LEW) bone marrow (BM) infusion or an orthotopic liver allograft (OLT) and a short. 2-week course of immunosuppression with Tacrolimus.…”

mentioning

confidence: 99%

The immunolymphatic theory of chronic rejection

Demetris

Murase

Fung

et al. 1997

Transplantation Proceedings

View full text Add to dashboard Cite

Chronic rejection (CR) primarily manifests itself as a progressive obliterative arteriopathy (OA) that most frequently affects medium-sized muscular arteries of vascularized organ allografts. The lack of similar changes in isografts argues strongly for an immunologic basis. The most widely accepted hypothesis proposed to explain CR suggests that direct immunologic injury to the graft endothelium mediated by alloreactive cells and/or antibodies triggers a vascular wall repair response driven by cytokines and growth factors. It will be referred to here as the "direct injury" model. This response can be made worse by hyperlipidemia or ameliorated by drugs that block the immunologic insult or the vessel wall response.Despite successful application of this line of reasoning, several morphologic observations on failed allografts with CR are not readily explained by the direct injury model, as illustrated by the following examples: (1) OA preferentially involves medium-sized muscular arteries with accentuation of the changes near first and second order branch points; (2) OA changes are less severe in smaller arteries and veins, despite an antigenically similar endothelium; (3) OA is not a complication of graft-versus-host disease, despite being an immunologic mirror image of rejection; (4) OA is not always preceded by intimal inflammation or endothelial disruption detectable by light microscopy; (5) mechanical factors in medium-sized arteries are not conducive to lymphocyte attachment and exocytosis, except during severe immunologic reactions; (6) the reasons for an antigen-dependent and antigen-independent phases of OA are not readily apparent. Many of these peculiarities suggest that mechanical factors also contribute to the development of OA. Moreover, the direct injury model does not address the immunopathogenic mechanisms responsible for the persistent immunologic injury.An effort has been made in recent years by our group to reconcile these inconsistencies in clinical tissue samples and a small animal model of CR, which was inadvertently uncovered while conducting experiments on the significance of microchimerism. 1,2 In that model, Brown-Norway (BN) rats are pretreated with a Lewis (LEW) bone marrow (BM) infusion or an orthotopic liver allograft (OLT) and a short. 2-week course of immunosuppression with Tacrolimus. 3 These pretreated recipients are then challenged 100 days later with a heterotopic LEW heart allograft without immunosuppression.The heart grafts in both groups undergo a transient acute rejection between 5 and 15 days, marked by an influx of inflammation and an upregulation of both Th1-and Th2-type cytokine mRNA as detected by RT-PCR. Although all of the rats are operationally tolerant, in that the heart allografts are accepted and are beating for 100 days, 3 progressive CR and OA develop by 60 to 100 days in the challenge heart grafts of BM-pretreated recipients but not in those conditioned with OLT.Address reprint requests to A.J. Demetris,

show abstract

Infectious pulmonary disease in patients receiving immunosuppressive therapy for organ transplantation

Starlz

1999

Rev. Med. Virol.

View full text Add to dashboard Cite

Transplantation Milestones

Cited by 32 publications

References 8 publications

The lost chord: microchimerism and allograft survival

The lost chord: microchimerism and allograft survival

The immunolymphatic theory of chronic rejection

Infectious pulmonary disease in patients receiving immunosuppressive therapy for organ transplantation

Contact Info

Product

Resources

About