Long survival in rats after multivisceral versus isolated small-bowel allotransplantation under FK 506

Abstract

Abdominal multivisceral allotransplantation (MVTX) from Brown Norway donor rats to Lewis recipient rats was performed under a 14-day course of low (0.32 mg/kg) or high-dose (0.64 mg/kg) intramuscular FK 506 to which weekly further injections were added in some of the high-dose animals. With all three regimens, long survival was frequently achieved with good intestinal adsorption and weight gain, but histopathologic evidence of intestinal rejection existed in the most lightly treated animals. The liver, stomach, and pancreas had only minor abnormalities. Rejection of isolated intestinal grafts was more difficult to control based on histopathologic criteria, and satisfactory results were obtained only with the most aggressive treatment protocol, suggesting that the liver in the MVTX had provided an advantage to the companion organs of the graft, of which the intestine was most vulnerable. Histopathologically, the lymphoid elements of the intestine, including the Peyer's patches, appeared to be the most immunogenic component of the intestine. Epithelium near lymphoid areas was secondarily involved with villous atrophy, cryptitis, and abscess formation. Beginning within 12 days in successful MVTX experiments, the lymphoreticular components of the graft intestine, including the Peyer's patches, lamina propria, and mesenteric nodes, were shown with anti-Ia monoclonal antibodies to be repopulated with recipient cells. This finding in grafts that appeared to be permanently accepted was surprising and contrary to expectations from the literature on intestinal allotransplantation.

Fig. 1

Body weight (mean) after transplantation for each treatment group. Weight gain was significantly better (p < 0.05 Student t test) in the pooled MVTX animals versus pooled SBTX animals at the times indicted (^*) and also in the low dose experiments at the single time noted.

Fig. 2

Maltose absorption test (mean ± SD) of MVTX and SBTX recipients with short term high dose FK506 treatment.

Fig. 3

At 203 days after MVTX under high dose continuous FK 506 (group 4). A, Essentially normal small intestine and intact Peyer’s patches. (Hematoxylin-eosin; original magnification ×48. ) B, Pancreas with mild periductular mononuclear infiltrate (arrow). (Hematoxylin-eosin; original magnification ×125.)

Fig. 4

At 134 days after MVTX under high dose FK 506 for 14 days only (group 3). A, Normal intestine and Peyer’s patches. (Hematoxylin-eosin; original magnification ×48.) B, Intact mesenteric lymph node with full complement of lymphoid cells. (Hematoxylin-eosin; original magnification ×48.)

Fig. 5

Intestine 107 days after SBTX under high dose FK 506 for 14 days only (group 7). The conditions of treatment were the same as for the MVTX group 3 (compare with Fig. 4). A, Villous blunting, scarring at Peyer’s patch remnant (arrow) and thickening of muscularis. (Hematoxylin-eosin; original magnification ×48.) B, Mucosal breakdown and intramural abscess (arrow) at site of Peyer’s patch disappearance. (Hematoxylin-eosin; original magnification magnificatoin ×48.) C, High power or abscess. (Hematoxylin-eosin; original magnification ×300.)

Fig. 6

Host (A) and graft (B) mesenteric lymph nodes from the same rat as in Fig. 5, 107 days after SBTX. Note the total lymphoid depletion and extensive scarring of the allograft node in which remnants of the subcapsular sinus can be seen (arrow). (Hematoxylin-eosin; (hematoxylin-eosin; original magnification ×48.)

Fig. 7

Replacement of intensely L-21-6+ spindle-shaped cells was noted in the liver of a MVTX recipient killed for histologic study 114 days after transplantation under transplantation under high dose FK 506 for 14 days only on (group 3). These cells are probably bone marrow–derived dendritic cells. (L-21-6, red with hematoxylin counterstain; original magnification ×300.); pv, Portal vein.

Fig. 8

Replacement of the donor lymphoid tissue with recipient cells. A, Twelve days after MVTX under high-dose FK 506 for the 12 days of survival (group 3) about one half of the intestinal lymphoid cells were replaced (L-21-6, red; hematoxylin hematoxyling counterstain). B, At 114 days (group 3), most of the cells in the follicles of the Peyer’s patches displayed recipient Ia determinants. C, Same replacement in the lamina propria of the villi (group 3) at 134 days. (L-21-6, red; hematoxylin counterstain; original counterstain (original magnification X300.) T, T-cell interfollicular zone; F, B-cell follicle.