Demetris, AJ

Starzl, TE

Trucco, M

PubMed

Name not available

Matching and the black recipient

D-Scholarship@Pitt

IL Matching and the Black Recipient T.E. Starzl, A.J. Demetris, and M. Trucco WE WILL TRY to show how new insight into the mechanism of graft acceptance makes possible the reexamination of the UNOS policy of cadaver kidney allocation primarily by tissue matching criteria. Because matching is only marginally relevant to outcome. the present practices are prejudicial to the minority recipients of this country without a quantum gain in efficient organ use. A successful transplant was long envisioned as an alien patch in a homogeneous hostile sea. This changed for the liver in 1969 when karyotyping studies in human female recipients of male hepatic allografts showed that the entire macrophage system. including the Kupffer cells. was re-placed with recipient female cells within 100 days.l.2 This graft chimerism was assumed to be a special feature of the liver for more than 20 years. The illusion of the liver's uniqueness was dispelled in 1991 with the demonstration that transplanted intestines in ratsJ and humans4 became permanently chimeric within a few weeks; the same find-ings were soon verified in other transplanted organs. Between 1991 and now. it was discovered what hap-pened to the donor leukocytes replaced in the liver. intestinal. and other grafts. A combination of clinical and experimental observations (summarized in ref 5) showed that these donor cells leave the graft within minutes and pass into the lymphoid organs including the thymus. Un-der effective immunosuppression in rats (and probably somewhat later in humans). they disperse ubiquitously after 2 to 4 weeks and thereafter can be found in the heart. skin. and elsewhere. With organs vascularized by surgical anastomosis. the primary cell migration is vascular. with prompt secondary inclusion of the lymphatic circulation. Multiple lineages of chimeric cells home to areas of lymphoid organs where syngeneic cells of the same lineages normally traffic.6 For example. in the thymus. macrophages and dendritic cells show up in the medulla with T and B cells in the follicles. At first, the thymic cortex is donor cell free. In the lymph nodes. B cells are home to follicles. T cells to the T -lym-phocyte-rich paracortex. and macrophages and dendritic cells to both medulla and paracortex. The spleen traffic conforms to the substructure of the periarterial sheath anatomy. After the cells break out of the lymphoid organs. they spread ubiquitously and. in human cases. can be found 20 and 30 years later in the skin. lymph nodes. and elsewhere. Under immunosuppression. these events apparently lead to a body-wide mutual engagement. activation. and ultimately clonal "silencing" of both donor and recipient immunocytes.5•7 These cell interactions are thought to play a crucial role in the "acceptance" of allo- and ,5 teO xenografts under immunosuppression and to participate in the first step of the induction of donor specific nonrcactiv-ity. The nonreactivity which resembles the "infectious" tolerance described in a recent Science article by Wald-manns also develops the other way round. explaining the rarity of graft-versus-host disease (GVHD) in human re-cipients of both intestinal and liver grafts that contain a dense migratory leukocyte component. Systemic chimerism has been most extensively studied after liver transplantation.9 It was demonstrated in all 2S liver recipients studied in 1992. 2 to 22 years after liver transplantation, either by finding donor cells in peripheral tissue with immunostaining by donor-specific HLA anti-bodies or by identifying donor DNA by polymerase chain reaction (peR); and in nine female recipients of male livers by the presence of the Y chromosome in these tissues with cytostaining or peR technologies. Relevant to today's discussion. the same systemic chi-merism was demonstrated in five patients studied after they had borne their continuously well-functioning kidney transplants for nearly 30 years posttransplantation. 10 All were HLA mismatched and thus could be studied (along with their donors) by finding the HLA alleles in peripheral tissues with immunostaining or peR. Viable donor cells that appeared to be dendritic cells were found in the lymph nodes and skin of all of these kidney recipients and then confirmed with peR. Under the conditions of clinical whole organ transplan-tation. we have postulated and obtained evidence of cel-lular interactions (graft-versus-host and host-versus-graft) that we have called mutual natural immunosuppression. These are envisioned as occurring on a sliding scale in which each further level of histoincompatibility provokes countervailing increases in the initial immune response. This initial response is genetically controlled. However, if the acute storm can be weathered long enough to allow a rapprochement under the protective umbrella of modem day immunosuppression. the anticipated typing effect rap-idly dwindles. We think that this explains the poor corre-lation of tissue matching with outcome after all kinds of From the Pittsburgh Transplant Institute. and the Departments of Surgery. Pathology. and Pediatrics, University of Pittsburgh Health Science Center, Pittsburgh. Pennsylvania. Supported by Project Grant No OK 29961 from the National Institutes of Health. Bethesda, Maryland. Address reprint requests to Thomas E. Starzt. MD. PhD. De-partment of Surgery, 3601 Filth Avenue. 5C Falk Clinic. University of Pittsburgh. Pittsburgh. PA 15213. ~ 1993 by Appleton & Lange 0041-13451931S3.00I +0 2450 Tranaplantation Prooeedings, Vol 25. No 4 (August), 1993: pp 2450-2451 MATCHING AND THE BLACK RECIPIENT whole organ cadaver transplantation, short of a perfect match.s.7.9 As to matching, it has been 27 years since the first prospective trials of HLA matching in kidney transplanta-tion were begun by our team at the V niversity of Colorado in collaboration with Dr Paul Terasaki of VCLA. II The logical assumption was made that this kind of donor-recipient pairing would be a definitive way of improving the results. The anticipated results were obtained with perfectly matched siblings, but not with other donor-recipient pairings. 12 However, the power of anticipation that the same thing would apply in unrelated cases with lesser degrees of matching has been so great that it has not been shaken. in spite of the fact that thousands of confiicting reports have not allowed this question to come to scientific closure. A matching effect either has not been found or even in the most optimistically presented large collections has been confined to a few percentage points mounted on the successes without matching that have become greater and greater over the years. Matching as a guide for organ deployment has been thought by many to endow little or no advantage to the cadaveric-kidney recipient except when there is a perfect match and to have become an instrument of social injus-tice. specifically affecting the black patient whose chances of obtaining a good match and therefore a kidney are diminished. 13 •14 Armed with the paradigm shift in under-standing of matching that derives from the mechanisms we have described. the time has come to address this issue with a different approach than the usual fiery debate between those lined up on one side or the other side of the matching issue. There is more at stake than matching per se. The naturally occurring postoperative cell migration and repop-ulation responsible for graft acceptance can be augmented 2451 perioperatively by infusion of donor bone marrow, blood (donor specific transfusion), and presumably other donor leukocyte sources including the spleen. This could build up the conditions for leukocyte-poor organs (like the kidney and heart) to the immunologic advantage enjoyed by the tolerogenic liver.S.7.9.IO It is ironic that the present HLA-dominated VNOS distribution scheme with its quasi-legal status, emphasis on matching, and necessity for kidney transport is the single greatest logistic impediment to the exploitation of this next and much needed phase of devel-opment. REFERENCES I. Porter KA: In Starzl TE (ed): Experience in Hepatic Trans-plantation. Philadelphia. Saunders. 1969. p 464 2. Kashiwagi N. Porter KA. Penn I. Starzl TE: Surg Forum 20:374. 1969 3. Murase N, Demetris AJ. Matsuzaki T. et al: Surgery 110:87. 1991 4. Iwaki Y. Starzl TE. Yagihashi A. et al: Lancet 337:818. 1991 5. Starzl TE. Demetris AJ. Murase N. et al: Immunol Today 14:326. 1993 6. Demetris AI. Murase N. Fujisaki S. et al: J Exp Med (in press) 7. Starzl TE. Demetris AJ. Murase N. et al: Lancet 339:1579. 1992 8. Qin S. Cobbold SP. Pope H. et al: Science 259:974. 1993 9. Starzl TE. Demetris AJ. Trucco M. et al: Hepatology 17:1127. 1993 10. Starzi TE. Demetris AI. Trucco M. et al: Transplantation 55:1272. 1993 II. Terasaki PI. Vredevoe DL. Mickey MR. et al: Ann NY Acad Sci 129:500. 1966 12. Stant TE. Porter KA. Andres G. et al: Ann Surg 172:437. 1970 13. Starzi TE. Shapiro R. Teperman L: Transplant Proc 21(suppl 3):3432. 19!!9 14. Guttmann R: Transplant Proc 24:2407. 1992 

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Matching and the black recipient

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