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Patchy distribution of rejection changes in small intestinal transplantation
Patchy
Distribution ByA. Yamataka,
of Rejection Changes Transplantation
in Small
Intestinal
T. Miyano, K. Fukunaga, H. Kobayashi, M. Nozawa, and K. Sasaki
Tokyo, Japan; Saitama, Japan; and Yokohama, Japan l The aim of this study is to determine the distribution of histological changes of rejection in small intestinal transplantation. Thirty-nine rats were randomized into two groups: group I (n = 15), syngeneic transplants and group II [n = 24), allogeneic transplants. Grafts were excised and examined on days 2, 4, and 8 after transplantation. All grafts of the syngeneic group showed normal mucosa by day 4. However, by this time, all grafts of the allogeneic group demonstrated rejection changes with a patchy distribution in the mucosa. Therefore, with a biopsy from the stoma site there is a risk of missing early rejection. Copyright o 1992 by WA Saunders Company INDEX WORDS:
Intestinal transplantation.
I
N SMALL intestinal transplantation, random biopsy from the stoma site’.2 has been recommended as the most reliable test of monitoring early rejection. However, there is a risk of failing to diagnose early rejection, because rejection appears to occur in a patchy distribution. Using a rat small intestinal transplantation model, we examined the distribution of rejection changes.
Fig 1. Intestinal mucosa on day 4 after allogeneic transplantation showing the patchy distribution of rejection (original magnification x5). One area (arrowheads) demonstrates mucosal edema, cellular infiltration, crypt hyperplasia, vasculitis, and fibrosis, which are strongly suggestive of rejection (grade 3). However, on the left (arrows), the normal architecture of the mucosa is preserved.
severe lymphatic infiltration, mucosal sloughing, vasculitis with bleeding, marked fibrosis. RESULTS
MATERIALS AND METHODS Thirty-nine inbred WistariShi rats weighing 250 to 300 g were randomized into two groups: group I (n = 15) received syngeneic transplants, group II (n = 24) received allogeneic transplants from rats of a Lewis strain. The operative techniques were similar to those previously described by Monchik and Russell.3 The distal ends of the donor intestines were brought out through the abdominal wall as stomas. Five rats of group I and eight rats of group II were killed on days 2, 4, and 8 after transplantation. Segments of intestinal grafts (7 x .5 cm) from the distal stoma onward were tied in 10% formalin. These segments were stained with hematoxilin and eosin and the whole specimen was examined histologically. The histological criteria for rejection used were: blunting of the villi, lymphatic infiltration, crypt hyperplasia, mucosal sloughing, vasculitis, and fibrosis. Rejection was graded as follows: grade 1, minimal lymphatic infiltration; grade 2, mild lymphatic infiltration, crypt hyperplasia, blunting of the villi with edema; grade 3, severe lymphatic infiltration, crypt hyperplasia, marked blunting of the villi, vasculitis, fibrosis; and grade 4, very
The mucosa of all grafts in group I appeared normal apart from minor ischemic changes on day 2 after transplantation. On days 4 and 8, the mucosa of all grafts was normal. In group II, on day 2 after transplantation, the mucosa of all grafts showed similar histological features to group I. However, on day 4 some areas in the mucosa of all grafts showed rejection (grade 2 to 3) but at other places they appeared normal (Fig 1). On day 8, five of the eight animals showed diffuse changes of rejection (grade 3 to 4). However, the other three animals still demonstrated rejection with a patchy distribution as seen on day 4. The abovementioned results are summarized in Table 1. Table 1. The Mucosal Conditions of the Grafts Days Posttransplant
From the Department of Pediafric Surgery, Juniendo University School of Medicine, Tokyo, Japan; the Department of Surgery, Meikai University, Saitama, Japan; and the Department of Anatomy, Yokohama City University School of Medicine, Yokohama, Japan. Date accepted: November 27, 1990. Address reprint requests to A. Yamataka, MD, Depattmenf of Pediatric Surgery, Juntendo University School of Medicine, 2-1-I Hongo, Bunkyo-ky Tokyo 113, Japan. Copyright o I992 by W.B. Saunders Company 0022-3468192/2705-0017$03.00/0 602
Group I (I-I = 15)
Group iI (n = 24)
Day 2
Day4
Day 8
N:5
N:5
N:5
P:O
P:O
P:O
R:O
R:O
R:O
NY8
N:O
N:O
P:O
P:8
P:3
R:O
R:O
R:5
Abbreviations: N, normal mucosa; P, rejection with a patchydistribution; R, rejection with a diffuse distribution.
JournalofPediatric Surgery, Vol 27, No 5 (May), 1992: pp 602-603
REJECTION CHANGES IN SMALL
BOWEL TRANSPLANT
603
DISCUSSION
In small intestinal transplantation, serial biopsies from the stoma site are currently the recommended test of detecting early graft rejection.’ However, it is doubtful whether this histological test gives us precise information about early rejection. Lee et al4 reported that histological changes seen on stoma biopsy were not always specific for rejection even 8 days after transplantations, because only four of eight animals showed definite histological signs of rejection. Holmes et al5 considered that early histological changes are
caused by a perioperative ischemic period rather than by early rejection. They also noted that signs of rejection did not become apparent until 5 days after transplantation. The present study showed that intestinal rejection occurs with a patchy distribution. Therefore, histological analysis of a stoma biopsy specimen alone is inadequate and may fail to detect the onset of early rejection. ACKNOWLEDGMENT We are most grateful to Dr Daan den Hollander assistance with the manuscript.
for his
REFERENCES 1. Cohen Z, Nordgren S, Lossing A, et al: Morphological studies of intestinal allograft rejection: Immunosuppression with cyclosporine. Dis Colon Rectum 27:228-234, 1984 2. Lossing A, Nordgren S, Cohen Z, et al: Histological monitoring of rejection in small intestinal transplantation. Transplant Proc 14:643-645, 1982 3. Monchick GJ, Russell PS: Transplantation of small bowel in
the rat: Technical and immunological considerations. Surgery 70:693-102,197l 4. Lee MD, Smith SD, Yunis EJ, et al: In vivo transmural potential difference: An early monitor of rejection in small bowel transplantation. J Pediatr Surg 24:767-770, 1989 5. Holmes JT, Yeh SDJ, Winawer SJ, et al: Absorption studies in canine jejunal allografts. Ann Surg 174:101-108, 1971
Distribution ByA. Yamataka,
of Rejection Changes Transplantation
in Small
Intestinal
T. Miyano, K. Fukunaga, H. Kobayashi, M. Nozawa, and K. Sasaki
Tokyo, Japan; Saitama, Japan; and Yokohama, Japan l The aim of this study is to determine the distribution of histological changes of rejection in small intestinal transplantation. Thirty-nine rats were randomized into two groups: group I (n = 15), syngeneic transplants and group II [n = 24), allogeneic transplants. Grafts were excised and examined on days 2, 4, and 8 after transplantation. All grafts of the syngeneic group showed normal mucosa by day 4. However, by this time, all grafts of the allogeneic group demonstrated rejection changes with a patchy distribution in the mucosa. Therefore, with a biopsy from the stoma site there is a risk of missing early rejection. Copyright o 1992 by WA Saunders Company INDEX WORDS:
Intestinal transplantation.
I
N SMALL intestinal transplantation, random biopsy from the stoma site’.2 has been recommended as the most reliable test of monitoring early rejection. However, there is a risk of failing to diagnose early rejection, because rejection appears to occur in a patchy distribution. Using a rat small intestinal transplantation model, we examined the distribution of rejection changes.
Fig 1. Intestinal mucosa on day 4 after allogeneic transplantation showing the patchy distribution of rejection (original magnification x5). One area (arrowheads) demonstrates mucosal edema, cellular infiltration, crypt hyperplasia, vasculitis, and fibrosis, which are strongly suggestive of rejection (grade 3). However, on the left (arrows), the normal architecture of the mucosa is preserved.
severe lymphatic infiltration, mucosal sloughing, vasculitis with bleeding, marked fibrosis. RESULTS
MATERIALS AND METHODS Thirty-nine inbred WistariShi rats weighing 250 to 300 g were randomized into two groups: group I (n = 15) received syngeneic transplants, group II (n = 24) received allogeneic transplants from rats of a Lewis strain. The operative techniques were similar to those previously described by Monchik and Russell.3 The distal ends of the donor intestines were brought out through the abdominal wall as stomas. Five rats of group I and eight rats of group II were killed on days 2, 4, and 8 after transplantation. Segments of intestinal grafts (7 x .5 cm) from the distal stoma onward were tied in 10% formalin. These segments were stained with hematoxilin and eosin and the whole specimen was examined histologically. The histological criteria for rejection used were: blunting of the villi, lymphatic infiltration, crypt hyperplasia, mucosal sloughing, vasculitis, and fibrosis. Rejection was graded as follows: grade 1, minimal lymphatic infiltration; grade 2, mild lymphatic infiltration, crypt hyperplasia, blunting of the villi with edema; grade 3, severe lymphatic infiltration, crypt hyperplasia, marked blunting of the villi, vasculitis, fibrosis; and grade 4, very
The mucosa of all grafts in group I appeared normal apart from minor ischemic changes on day 2 after transplantation. On days 4 and 8, the mucosa of all grafts was normal. In group II, on day 2 after transplantation, the mucosa of all grafts showed similar histological features to group I. However, on day 4 some areas in the mucosa of all grafts showed rejection (grade 2 to 3) but at other places they appeared normal (Fig 1). On day 8, five of the eight animals showed diffuse changes of rejection (grade 3 to 4). However, the other three animals still demonstrated rejection with a patchy distribution as seen on day 4. The abovementioned results are summarized in Table 1. Table 1. The Mucosal Conditions of the Grafts Days Posttransplant
From the Department of Pediafric Surgery, Juniendo University School of Medicine, Tokyo, Japan; the Department of Surgery, Meikai University, Saitama, Japan; and the Department of Anatomy, Yokohama City University School of Medicine, Yokohama, Japan. Date accepted: November 27, 1990. Address reprint requests to A. Yamataka, MD, Depattmenf of Pediatric Surgery, Juntendo University School of Medicine, 2-1-I Hongo, Bunkyo-ky Tokyo 113, Japan. Copyright o I992 by W.B. Saunders Company 0022-3468192/2705-0017$03.00/0 602
Group I (I-I = 15)
Group iI (n = 24)
Day 2
Day4
Day 8
N:5
N:5
N:5
P:O
P:O
P:O
R:O
R:O
R:O
NY8
N:O
N:O
P:O
P:8
P:3
R:O
R:O
R:5
Abbreviations: N, normal mucosa; P, rejection with a patchydistribution; R, rejection with a diffuse distribution.
JournalofPediatric Surgery, Vol 27, No 5 (May), 1992: pp 602-603
REJECTION CHANGES IN SMALL
BOWEL TRANSPLANT
603
DISCUSSION
In small intestinal transplantation, serial biopsies from the stoma site are currently the recommended test of detecting early graft rejection.’ However, it is doubtful whether this histological test gives us precise information about early rejection. Lee et al4 reported that histological changes seen on stoma biopsy were not always specific for rejection even 8 days after transplantations, because only four of eight animals showed definite histological signs of rejection. Holmes et al5 considered that early histological changes are
caused by a perioperative ischemic period rather than by early rejection. They also noted that signs of rejection did not become apparent until 5 days after transplantation. The present study showed that intestinal rejection occurs with a patchy distribution. Therefore, histological analysis of a stoma biopsy specimen alone is inadequate and may fail to detect the onset of early rejection. ACKNOWLEDGMENT We are most grateful to Dr Daan den Hollander assistance with the manuscript.
for his
REFERENCES 1. Cohen Z, Nordgren S, Lossing A, et al: Morphological studies of intestinal allograft rejection: Immunosuppression with cyclosporine. Dis Colon Rectum 27:228-234, 1984 2. Lossing A, Nordgren S, Cohen Z, et al: Histological monitoring of rejection in small intestinal transplantation. Transplant Proc 14:643-645, 1982 3. Monchick GJ, Russell PS: Transplantation of small bowel in
the rat: Technical and immunological considerations. Surgery 70:693-102,197l 4. Lee MD, Smith SD, Yunis EJ, et al: In vivo transmural potential difference: An early monitor of rejection in small bowel transplantation. J Pediatr Surg 24:767-770, 1989 5. Holmes JT, Yeh SDJ, Winawer SJ, et al: Absorption studies in canine jejunal allografts. Ann Surg 174:101-108, 1971