Accommodation of grafts: Implications for health and disease
Section snippets
Accommodation in clinical transplantation
Accommodation is sometimes considered an unusual outcome of transplantation, if it is considered at all. For example, the attendees at a consensus conference of the National Institutes of Health on antibody-mediated rejection considered accommodation “a latent response” or “silent humoral rejection” [13]. In the report of the most recent Banff Conference on the pathology of organ transplants, accommodation is mentioned in the text but not listed in the table of outcomes of kidney
Explaining “the paradox” of frequent accommodation and low prevalence of anti-HLA antibodies
Anti-HLA antibodies are generally considered detrimental for organ transplants, and the presence of these antibodies in the blood of a transplant recipient predicts rejection [17], [18], [19], [20]. Consistent with the concept, anti-HLA antibodies are detected infrequently in individuals with normally functioning transplants. Hence, if the operational definition of accommodation (normal graft function in a recipient with antibodies specific for the graft) is applied, accommodation must be
Accommodation in experimental models
We explored accommodation in experimental organ transplants for nearly 2 decades. Generally, the model systems used involve the transplantation of organs between disparate species, and the recipients of these transplants had natural and acquired antibodies specific for the grafts [11], [21], [22]. In the model systems we reported depletion of all immunoglobulin or species-specific immunoglobulin could allow survival of the organ graft and accommodation to ensue (Figure 1)[23], [24]. Figure 1
Estimating the prevalence of accommodation in clinical organ transplantation
Given the experimental results described above, we suggest several provisional concepts. First, the operational definition of accommodation (normal graft function in those with anti-donor antibodies in the circulation) probably misses accommodation in many cases. Second, accommodation might also occur but escape detection because anti-donor antibodies are cleared from the circulation and from graft cells. To address the limitation we tried to use the presence of C4d bound to a graft in the
The fate of bound antibody and mechanisms of accommodation
Understanding how accommodation occurs and by what mechanism it is manifested is of obvious importance in clinical transplantation, transplantation biology, and, more broadly, immunology [29], [30]. We pursued the question using experimental model systems.
To explore the fate of antibody bound to grafts we used cultured endothelial cells as a model system. Cultured endothelial cells are recognized by antibodies specific for the source of a graft [11], [31]. Antibodies bound to metabolically
Toward a broader concept of accommodation
Acquired resistance to injury, as such, can be found in many biological systems [63], [64], [65], [66]. It is unknown which, if any, of these systems represents pathways or mechanisms by which grafts acquire resistance to injury in accommodation. For example, treatment of drosophila with dichlorodiphenyltrichloroethane-induced production of cytochrome P450 and possibly other genes that confer resistance to further exposure to this toxic substance [67], although other genes must be involved [68]
Toward a new definition of accommodation
Identifying and understanding accommodation depends on the development of a more compressive and sensitive definition of the condition. Clearly, the operative definition mentioned above (presence of anti-donor antibodies in a patient with normal graft function) may fail to detect many instances of accommodation, and in fact the definition may identify the exceptional cases when antibody is not effectively cleared by the graft. A rigorous working definition of accommodation in experimental
Conclusions
Accommodation should be pursued in those settings in which it is thought to occur naturally. For example, Segev et al. [73] recently reported on the transplantation of ABO-incompatible kidneys in four patients with relatively high levels of isohemagglutinins specific for the graft. The patients all had detectable isohemagglutinins, although at low titers after transplantation, and perhaps accommodation. How these kidneys change over time might provide clues about what sustains accommodation and
Acknowledgments
The work was supported by grants from the National Institutes of Health (HL079067, HL52297, and GM96922).
References (79)
- et al.
Antibody, complement and accommodation in ABO-incompatible transplants
Curr Opin Immunol
(2004) - et al.
Isohemagglutinins and xenoreactive antibodies are members of a distinct family of natural antibodies
Hum Immunol
(1996) - et al.
Transplantation of discordant xenografts: a review of progress
Immunol Today
(1990) - et al.
National conference to assess antibody-mediated rejection in solid organ transplantation
Am J Transplant
(2004) - et al.
Banff’05 meeting report: differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy (‘CAN’)
Am J Transplant
(2007) - et al.
Serum analysis after transplant nephrectomy reveals restricted antibody specificity patterns against structurally defined HLA class I mismatches
Transpl Immunol
(2005) - et al.
Serial ten-year follow-up of HLA and MICA antibody production prior to kidney graft failure
Am J Transplant
(2005) - et al.
Alloantibodies and the outcome of cadaver kidney allografts
Hum Immunol
(2006) - et al.
Determinants of poor graft outcome in patients with antibody-mediated acute rejection
Am J Transplant
(2007) - et al.
Xenoreactive natural antibodies in the world of natural antibodies: typical or unique?
Transpl Immunol
(1995)