Immunomodulation for intestinal transplantation by allograft irradiation, adjunct donor bone marrow infusion, or both.

BACKGROUND: The passenger leukocytes in the intestine have a lineage profile that predisposes to graft-versus-host disease (GVHD) in some animal models and have inferior tolerogenic qualities compared with the leukocytes in the liver, other solid organs, and bone marrow. Elimination by ex vivo irradiation of mature lymphoid elements from the bowel allografts is known to eliminate the GVHD risk. We hypothesized that infusion of donor bone marrow cells (BMC) in recipients of irradiated intestine would improve tolerogenesis without increasing the risk of GVHD. METHODS: Orthotopic small intestine transplantation was performed with the GVHD-prone Lewis (LEW)-to-Brown Norway (BN) combination and the reverse GVHD-resistant BN-to-LEW model under a short course of tacrolimus treatment (1 mg/kg/day, days 0-13, 20, 27). Grafts were irradiated ex vivo, using a 137Cs source. In selected experimental groups, donor BMC (2.5 x 10(8)) were infused on the day of small intestine transplantation. RESULTS: The unmodified LEW intestine remained intact, whether transplanted alone or with adjunct donor BMC infusion, but all of the BN recipients died of GVHD after approximately 2 months. Intestinal graft irradiation (10 Gy) effectively prevented the GVHD and prolonged survival to 92.5 days, but all of the BN recipients died with chronic rejection of the LEW grafts, which was prevented by infusion of adjunct donor BMC without causing GVHD. In the GVHD-resistant reverse strain direction (BN-->LEW), all intestinal recipients treated for 27 days with tacrolimus survived > or =150 days without regard for graft irradiation or adjunct BMC, but chronic rejection was severe in the irradiated intestine, moderate in the unaltered graft, and least in the irradiated intestine transplanted with adjunct BMC. Mild arteritis in the 150 day allografts of both strain combinations (i.e., LEW--> BN and BN-->LEW) may have been irradiation associated, but this was prevented when weekly doses of tacrolimus were continued for the duration of the experiment rather than being stopped at 27 days. CONCLUSIONS: Recipients are protected from GVHD by irradiating intestinal allografts, but the resulting leukocyte depletion leads to chronic rejection of the transplanted bowel. The chronic rejection is prevented with adjunct donor BMC without causing GVHD. Although application of the strategy may be limited by the possibility of radiation injury, the results are consistent with the paradigm that we have proposed to explain organ-induced graft acceptance, tolerance, and chronic rejection

Review of renal oncocytosis (multiple oncocytic lesions) with focus on clinical and pathobiological aspects

Renal oncocytosis is a recently established disease entity characterized by numerous oncocytic tumors and diffuse involvement of oncocytic changes in renal parenchymal epithelia. In this article, we review this disease with a focus on its clinical and pathobiological aspects. Clinically, renal oncocytosis may occur in a sporadic form without any underlying disease or may be associated with chronic renal failure/long-term hemodialysis. However, Birt-Hogg- Dubé syndrome, characterized by skin tumors such as fibrofolliculoma or trichodiscoma, pulmonary lesions including bullae and spontaneous pneumothorax, and renal tumors should be evaluated in the differential diagnosis. The disease can develop either unilaterally or bilaterally. The involved renal parenchyma contains several to multiple brownish-colored nodules of varying size and is entirely replaced by lesions at the overt stage. Histologically, oncocytic tumors in both the dominant mass and smaller lesions encompass so-called hybrid tumor, chromophobe renal cell carcinoma (RCC), and renal oncocytoma (RO). Regarding renal parenchymal abnormalities, infiltrative growth of oncocytic cells, cortical cysts with oncocytic features, or extensive oncocytic change in non-neoplastic tubules can also be observed. Histochemical, immunohistochemical, and molecular genetic features of chromophobe RCC and RO arising in the setting of renal oncocytosis are generally identical to those in the sporadic type. However, hybrid tumors seem to be histologically distinct from chromophobe RCC and RO. In FISH analyses of some hybrid tumors, a gain of chromosomes 1, 2, 6, 10, and 17 was identified. In one tumor, no germ line mutation of folliculin gene was identified. Published data show that tumors follow a benign course. Further studies will be necesary to clarify the pathogenesis of renal oncocytosis