Delaney, CP

Demetris, AJ

Fung, JJ

Murase, N

Starzl, TE

Woan, M

PubMed

D-Scholarship@Pitt

The Liver Allograft, Chronic (Ductopenic) Rejection, and Microchimerism: What Can They Teach Us? A.J. Demetris. N. Murase. C.P. Delaney, M. Woan, J.J. Fung. and T.E. Starzl THICKENING of the most internal layer of the arterial walls in a human allograft (arterial intimal fihromu~­dll;lr hyperplasia) was first reported in 1955 hy the pathol-1I!!I't Gustav Dammin. in collaboration with Hume. I Since I';cn. many different terms have heen used to describe this l'llmplication of allogeneic kidney transplantation: obliter-a\l\'c arteriopathy (OA). transplant atherosclerosis. trans-plant arteriopathy. and others. In 1963. Porter et al~ linked Ihis complication to a genetic disparity hetween the recip-Il'nl and the allograft. thus showing OA to be a specific suolype of rejection. widely known today as chronic rejec-lion. Although OA is the principal manifestation of chronic rl'lcclion in all organ allografts. other accompanying fea-IlIfl'S include interstitial and periarterial fibrosis and subse-llll.:111 atrophy or loss of parenchymal cells:~ Chronic rejee-i It'll of the liver. which is the focus of this presentation. has hC'c'n defined hy an international panel of experts. sane-tllllled hy the World Congresses of Gastroenterology4 as: a " ... usually irreversible process characterized by two his-topathologic features: obliterative vasculopathy and loss of oile ducts. Although these two components usually co-exist. they occasionally may occur independently. The process is elicited by a genetic disparity he tween the donor and the recipient. but other co-factors may he involved." FEATURES OF CHRONIC LIVER ALLOGRAFT REJECTION The arterial disease in liver allografts most commonly aneets medium and large-sized. first and second-order branches of the hepatic artery in the liver hilum.5- 1O The llIain feature is intimal thickening because of deposition of 11l;lcrophage and/or myointimal cells that are often stuffed wilh lipids. combined with more modest myofibroblast proliferation and collagen deposition.3 Endothelial cell hypertrophy, transmural inflammation of varying severity. medial thinning. and inflammation and sclerosis of the adventitia also are frequently seen. The thickened intima may contain inflammatory cells, like T and B lymphocytes, macrophages. and occasionally. dendritic cells that signal the presence of an ongoing immune reaction.3 . 11 Eventu-ally. the intimal thickening causes lumenal narrowing and diminished arterial blood flow to the dependent bile ducts. Small arterioles in the portal tracts are usually spared from Ihe intimal changes but may show medial hypertrophy ;lIldor hyalinization. When the OA in large perihilar arteries is severe. small pUrial tract arteries. arterioles. and capillaries in the pnibiliary arterial plexus may be completely destroyed. 12· 13 This results in compromised arterial flow to the dependent bile ducts. which can already be damaged or destroyed hy direct immunologic injuf)'. Moreover. progressive narrow-ing of the lumen of larger arteries predisposes them to thromhosis. which in turn can cause necrosis and/or stric-turing of large perihilar bile ducts. Damage and loss of small interlobular bile ducts is the second hallmark feature of chronic liver allograft rejec-tion.,,-'u4-1" This manifestation is generally considered to be of secondary importance hecause isolated duct loss can occur for other reasons. such as obstructive cholangiopathy and adverse drug reactions. Bile ducts normally are present in 750i: to 800;' or more of portal tracts containing a hepatic arterial branch. Theoretically. duct loss could be considered to he present when more than 25% of the portal tracts are devoid of a bile ducl. Unfortunately. in routine clinical practice difficulty with reproducing bile duct and/or portal tract counts. and sampling problems associated with a small biopsy of a large organ. necessitates using a more conser-vative figure of a 50% deficiency to be certain that there is ductopenia.4 RISK FACTORS AND PATHOPHYSIOLOGIC MECHANISMS OF INJURY Risk factors identified by different groups for the develop-ment of chronic rejection in the liver include multiple and/or poorly controlled acute cellular rejection episodes, chronic rejection in a previous failed allograft. a positive pre transplant Iymphocytotoxic crossmatch. anti-MHC anti-bodies that develop after transplantation. cytomegalovirus (CMV) infection. matching at the class II MHC locus and mismatching at the MHC class ] locus. non-Caucasian recipient race. chronic hepatitis virus infection. and treat-ment with a_interferon.6•7•11.l5.17-24 Hyperlipidemia. hyper-tension. diabetes. and preservation injury have. to our knowledge. not been associated with chronic rejection of the liver, but are thought to contribute to the development of OA in other solid organ allografts. Several groups including ours have suggested that the pathogenic mechanisms involved in the development of OA From the Pittsburgh Transplant Institute, Departments of Pathology (A.J.D.) and Surgery (NA, C.P.D., M.W., J.J.F., T.E.S.). Division of Transplantation, University of Pittsburgh, Pittsburgh, Pennsylvania. Address reprint requests to A.J. Demetris, Pittsburgh Trans-plant Institute, Department of Pathology, Division of Transplan-tation, University of Pittsburgh, Pittsburgh, PA 15213. © 1995 by Appleton & Lange 0041-1345/95/$3.00/+0 67 Transplantation Proceedings, Vol 27, No 1 (February). 1995: pp 67-70 68 include a response to injury. the same hypothesis as that used to explain the development of atherosclerosis in the general population.J·II.13.:!5.~6 Thus. attempts at classifica-tion are based on the nature of the initial insult. In an allograft. the cause of the injury appears to be primarily rooted in an allogeneic immune response. Likely arterial targets of this response include the endothelium. periarte-rial dendritic cells, and lymphatic capillary endothelium in the adventitia: disruption of the lymphatics could cause arterial wall edema. However. multiple other co factors. including preservation injury, viral infections (especially CMV), hyperlipidemia. hypercholesterolemia, hyperten-sion, and diabetes certainly could contribute to the insult and make worse the arterial disease. In any event. the arterial injury triggers a cascade of inflammation. growth and repair (explored in detail by Hayry and colleagues in this issue and elsewhere II) that eventually results in the characteristic OA described above. The second major target for injury in chronic rejection, the bile ducts, appears to be subjected to "double jeopar-dy", 13.~fi They are susceptible to direct immunologic injury from invading inflammatory cells and indirectly to ischemic damage because of arterial occlusion and destruction of the peribiliary capillary plexus.I~.IJ.2fi Direct injury via cytotoxic T lymphocytes (CTI..) is usually noted histopathologically and is one of the defining features of both acute and chronic rejection. In addition. cytokines locally released by the invading lymphocytes can either directly injure the ducts or recruit neutrophils and macrophages via chemotaxins that indirectly cause damage through release of oxidative prod-ucts. These same effector mechanisms can also destroy the small portal arterioles I J.~6 and fine webbing of capillaries I ~ that are the final conduit of arterial blood to the ducts. In addition, this unique portal microvasculature can be plugged and ruined by platelets and neutrophils in presen-sitized patients. ;O.27.2H explaining the association between preformed antibodies and bile duct loss. Lastly. Donaldson et al 21 have suggested that bile ducts can also contribute to their own destruction by acting as antigen-presenting cells (APC) when their class II MHC antigens are matched with the recipient. In vitro. we have shown that such a process is possible1,!: however. the duct cells are much less efficient antigen presenters than are endothelial cells tested in the same assay. RESISTANCE OF THE LIVER ALLOGRAFT TO CHRONIC REJECTION Primary allograft survival for the first 2 to 3 years after transplantation usually is worse for liver than for heart or kidney allograft recipients. After this. the survival curves for primary liver allografts begin 10 Hatten out between 3 and 5 years after transplantation whereas those for the heart and kidney show continual aurition. mostlv because of chronic rejection:1O This apparent difference i~ long-term allograft resistance to chronic rejection gleaned from survivall.:urves also surfaces at individual centers in studies of the struc-DEMETRIS. MURASE, DELANEY ET AL tural integrity and causes of late allograft dysfunction of liver vs other organs. Pappo et al;' 1 who studied the causes of liver allograft dysfunction in recipients who had survived for more than 5 years with the same liver. showed that recurrent viral hepatitis is more often responsible for late liver allograft dysfunction than either acute or chronic (ductopenic) re-jection.J1-J4 Obstructive cholangiopathy and recurrent al-cohol are also surprisingly common.JI In all studies of long-term survivors,31-34 rejection (acute andlor chronic) is found in less than 25% of patients with biochemical evi-dence of liver injury, and less frequently in asymptomatic patients with normal liver injury tests. Although these studies of long surviving recipients lend credence to the notion that a liver allograft is less suscep-tible than kidney or heart allografts to chronic rejection, Wight et al (this issue) have offered the alternative expla-nation that needle biopsy evaluation may underestimate the incidence of chronic rejection. This suggestion was not supported in a recent series of tolerance induction experi-ments by Murase et al35 that focused on microchimerism in rats. Experimental evidence was provided showing that liver allografts are more resistant to chronic rejection than hearts. It was shown that a liver allograft can protect another solid organ from the same donor from chronic rejection. 3s In these experiments, a 2-week course of FK 506 was able to induce acceptance for more than 100 days of a liver, heart. kidney, or bone marrow allograft. At first, these observations seemed an apparent contradiction to our recent hypothesis that microchimerism is a necessary pre-condition for the evolution of donor-specific tolerance:'o-.w All of these drug-free animals accepted at 100 days a challenge heart allograft from the same donor with survival for 100 more days without regard for the kind of primary transplant. and with or without hematolymphoid chimerism detectable by immunocytochemistry. However. examination of the surviving challenge cardiac grafts 1U0 days posttrans-plantation showed both multiple Quilty ksions~o and severe OA in the animals conditioned initially with a heart graft. In contrast. the challenge hearts in rats initially given a liver allograft of the same donor strain were completely pro-tected from chronic rejection and had no Quilty lesions or OA. In these experiments. the presence of hematolymphoid microchimerism in the reCipient correlated with resistance to chronic rejection, although the study design precluded exclusion of a role for hepatic parenchymal cells:15 At the end. we also concluded that we had developed a useful experimental model with which to study chronic rejection in the challenge grafts without interference from immunosup-pressive drugs. We helieve that protection from chronic rejection in this model is mediated by the multilineage donor hematolym-phoid cells that emigrate from the liver and persist in small numbers in the recipient:'h .. \7 .. ",.4I.~~ In essence. the hypoth-csis holds that a tiny fragment of the donor immune system. which is responsible for immunologic self-definition of the donor. integrates into the larger immunologic network of , i i I I i i I . LIVER ALLOGRAFTS the recipient.~Q.4' If this is correct. one might expect that other properties of the donor immune system. such as resistance to autoimmunity. could be transferred to the recipient as previously shown for delayed-type hypersensi-ti\itv reactions.~h riclaney et al44 recently tested this corollary hypothesis in liN rats which are susceptible to mercuric chloride-induced ;Iuwimmunity. LEW rats. which are resistant to HgCI~­Induced autoimmunity. were used as allogeneic bone mar-row donors. In this BN model. rejection of the allogeneic bone marrow is prevented by a 2-week course of FK 506. Although all immunosuppression is then stopped. rare (...::: I :3.0(0) donor LEW hematolymphoid cells continue to survive in the BN recipients for more than 100 days. These microchimeric recipients become almost totally resistant to the development of autoimmunity from the HgCI~ injec-tions.4~ These experimental observations may be relevant to the ohservation in long-term liver allograft survivors treated IlflL!inally for autoimmune chronic active hepatitis and f1f1marv biliarv cirrhosis (PBe) who have a low incidence .11lt! se~erity of recurrent disease.4h-~ I The potent immuno-'"ppression required to prevent rejection has been used to c);plain these findings. but the same lack of recurrence has been noted in patients weaned from immunosuppression.52 It may be that the immune stimulation and persistence of an integrated fragment of the donor's immune system analo-gous to that in the rat experiments is the critical protective factor. The discovery that the development of sustained micro-chimerism is an integral component of whole organ graft acccptance has opened many cryptic portals of transplan-tation immunology and has provided a rational explanation for chronic rejection. This concept will allow new insights ahout chronic rejection to be developed and subjected to dir<.:ct experimentation. Our prediction is that immunobio-IIl!.!lc manipulation of the recipient. such as the augmenta-tlun hv donor bone marrow that currentlv is being evaluat-nl" ciinically. will dispel the cloud of chr~nic reje~tion that 11:IS for so long darkened the horizon for kidney and heart allograft recipients. REFERENCES I, Hume DM. Merrill JP. Miller BF. et al: 1 Clin Invest 34:327. PISS ~, Porter KA. Thomson WB. Owen K. et al: Br Med 2:639.1963 ~, Dcmems AJ. Zerbe T. Banner B: Transplant Proc 21:3667. IIJKlJ 4, International Working Party: Liver Allograft Rejection (in pres, ) , Dcmetns Al. Laskv S. 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Druet P. Pelletier L. Rossert J. ct al: In: Kammuller ME. Bloksma N. Seinen W (eds). Autoimmune Reactions Induced bv Metals. Netherlands: Elsevier. 1989. p 347 . 46. Neuberger 1. Portmann B. MacDougall BRO. et al: N Engl J Med 306: 1. 1982 47. Neuberger J. Portmann B. Caine R. et al: Transplantation 37:363. 1984 DEMETRIS. MURASE. DELANEY ET AL 48. Demetris AJ. Markus BH. Esquivel C, et al: Hepatology 8:939. 1988 49. Balan V. Batts K. Porayko MK. et al: Hepatology 18:1392. 1993 50. Wright HL. Bou-Abboud CF. Hassanein T. et al: Transplan-tation 53: 136. 1992 51. Sanchez-Urdazpal L, Czaja AJ. Hoek BV, et al: Hepatology 15:215. 1992 52. Ramos HC, Reyes J. Abu-Elmagd K. et al: Transplantation (in press) 53. Fontes P. Rao A. Demetris AJ. et al: Lancet (in press) 

The liver allograft, chronic (ductopenic) rejection, and microchimerism: What can they teach us?

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The liver allograft, chronic (ductopenic) rejection, and microchimerism: What can they teach us?

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