Fung, JJ

Iwaki, Y

Kita, Y

Noguchi, K

Starzl, TE

Todo, S

Tzakis, AG

English

PubMed

D-Scholarship@Pitt

Daily Serum Inflammatory Cytokine (Tumor k~crosis ca~tor-aI Interleukin-6) Monitoring in Liver Transplantation Focusmg on Allograft Rejection: A Five-Case Report Y. Kita, Y. Iwaki, K. Noguchi, A.G. Tzakis, S. Todo, J.J. Fung, and T.E. Starzl L IVER allograft rejection is diagnosed largely base.d on liver function tests indicating graft damage associated with rejection. but histopathological diagnosis using biopsy is still necessarv. Since it can be difficult to distinguish rejection from ~ther causes of graft damage in the absence of liver histopathology. detection of a marker for immune activation and a mediator of inflammation could provide a noninvasive method of diagnosing rejection. Several studies have shown that the postoperative course of inflammatorv cvtokines such as tumor necrosis factor (TNF)-a' is pr~di~tive of rejection after human orthotopic liver transplantation. We have also previously shown that daily monitoring of serum or plasma interleukin Efi!-~ levels can be useful in predicting long-term graft prognosls.-However. few reports compare cytokine profiles after liver transplantation. Therefore. in this study. we monitored plasma and serum levels of cytokines in five transplant recipients who eventu-ally lost liver grafts because of relapsing rejection episodes. SUBJECTS AND METHODS FK 506 or cyclosporine (CyA). to which variable doses of methyl-prednisolone were added. wcre used in baseline immunosuppres-sion; OKT3 was given as indicated. Using ELISA. we monitored serum levels of IL-2. IL-6. TNF-a. and IL-l{3 in three liver transplant recipients and two abdominal organ-cluster transplant recipients who had experienced allograft rejection and eventually lost their liver allografts. ELISA involved a two-step sandwich enzyme immunoassay using Quantikine (Research and Diagnostic Systems Inc. Minneapolis. Minn) as described e1sewhere.2 Daily monitored cvtokine levels were evaluated and compared to clinical courses and ihe histopathological diagnosis of rejection. Serum and plasma levels were basically monitored daily around biopsy-proven rejection episodes. RESULTS Serum levels of IL-2. IL-lf3. and TNF-a in 30 healthy volunteers were all under detection. However. serum levels of IL-6of30heaJthyvolunteerswere 18:!: 34 pglmL (mean :!: SD). As shown elsewhere. l serum and plasma levels of IL-6 decreased after liver transplantation. regardless of pre trans-plantation values. Patients with infection subsequently de-veloped continuously high IL-6 levels. In patients without infection, significantly higher levels of IL-6 were usually found prior to the histopathological diagnosis of rejection. (L-6 elevations were spike-shaped, correlated poorly with the histological grade of rejection, and were highly respon-sive to augmented immunosuppression. In the five cases of rejection episodes we saw, serum IL-2 and IL-lf3 levels were not detected during the entire monitoring period. The elevations of serum TNF-a levels were similar to those for IL-6. Clinical courses and evalu-ations of serum IL-6 and TNF-a levels in five cases were shown as follows. Case 1 A 62-year-old man with alcoholic cirrhosis underwent or-thotopic liver transplantation (Fig I). His pretransplant plasma IL-6 level was high. but it was decreased after liver transplantation. The serum total bilirubin (TB) level also decreased as liver function improved. Liver biopsy on postoperative day (POD) 8 did not show acute cellular rejection (ACR). POD 16 to 17, showing that his liver function had recovered. Serum TB levels increased on POD 18, however, which indicate liver dysfunction due to ACR or some other cause. Liver biopsy performed on POD 19 showed moderate ACR. Soon after the diagnosis, intrave-nous administration of methylprednisolone (1 g x 5) was given. ACR was partially responsive to augmented immu-nosuppressive therapy, the graft was eventually lost. Con-cerning serum inflammatory cytokine profiles, spike-shaped elevation of IL-6 (>100 pglmL) was observed on POD 15. This pattern of elevation is characteristic of daily IL-6 monitoring. Interestingly, an elevation in TNF-a was also observed on POD 12. Case 2 A 48-year-old man with cryptogenic cirrhosis underwent orthotopic liver transplantation (Fig 2). His preoperative IL-6 level were also high but had normalized about 10 days after transplantation. Serum TB levels increased tempo-rarily after transplantation, possibly due to ischemic injury shown by biopsy on POD 5. Serum TB levels normalized on POD 20. A biopsy undertaken on POD 21 showed mild ACR, and a bolus methylprednisolone (1 g) was adminis-tered. Serum TB levels did not increase until POD 30. Biopsy on POD 29 showed severe ACR and soon after the diagnosis, OKT3 monoclonal antibody (10 mgld) was ad-From the Department of Surgery (Y.K .• A.G.T., S.T., J.J.F., T.E.S.) and Pathology (Y.I.. A.J.D .• K.N.). University of Pittsburgh, Pittsburgh, Pennsylvania. Address reprint requests to Thomas E. Starzl, MD, PhD, Department of Surgery, University of Pittsburgh, 3601 Fifth Ave, Pittsburgh, PA 15213. © 1996 by Appleton & lange 0041-1345/96/$3.00/ +0 Transplantation Proceedings, Vol 28, No 3 (June), 1996: pp 1237-1240 1237 I I I ! I i 1238 KITA. IWAKI. DEMETRIS ET AL 200 Case 1 10 Methyprednlsolone 1 g x 5 --0- fi~ _ TNF-alpha ~ ~ ~ + -TB 5 Fig 1. A 62-year-old man with alcoholic cirrhosis underwent liver transplantation. A moder-ate ACR episode occurred 2 weeks after transplantation. l+---~~-D~~~""~ee~~¥---~~=-~-----+l o ~ Biopsy findings No ACR ministered for 1 week. Eventually. however, the liver graft was lost due to other complications. Regarding the dynamic changes in IL-6 and TNF-a, as in case 1, an IL-6 spike was observed the same day the liver biopsy showed severe rejection. It is to be noted that the TNF-a spike appeared 3 days before the IL-6 spike, as shown in Fig 2. Case 3 A 36-year-old man with alcoholic cirrhosis underwent or-thotopic liver transplantation (Fig 3). He experienced an early-phase moderate AeR, which was proved by liver hiopsy on POD 4. On POD 5, an IL-6 spike was observed and holus methylprednisolone (I g) was administered. Since this rejection was treatment-resistant. OKT3 and steroid recycle therapy were tried. Biopsy on POD 19 still showed Case 2 400 ~ E --c;, 300 E: <II .c Q. (ij Ii. 200 Z .... cD ~ 100 Moderate ACR Partially treated No ACR ACR Postoperative days mild to moderate rejection. Plasma IL-6 levels were high and the pattern paralleled that of serum TB level. In this case, the TNF-a level was not determined in the earlier phase of rejection, but a very high level of TNF-a was observed after POD 20. Eventually, the graft was lost. Case 4 A 39-year-old woman with somatostatinoma of the pan-creas with liver metastasis underwent abdominal organ cluster transplantation (Fig 4). As early as POD 5, rejection was diagnosed clinically due to a progressive rise in serum TB (biopsy not performed) and a methylprednisolone bolus and OKT3 was initiated. This regimen was effective, but serum TB rose again from POD 11. An IL-6 spike was ohserved on POD 12 when steroid and OKT3 therapy was TNF .. lpha: 474 pg/ml Methylprednisolone 1 g • IL-6 OKT3 10 mg/day -TNF .. lpha TB -~ CI 15 §. c :c :l 10 == :c (ij 0 .... S Fig 2. A 48-year-old man With cryptogenic CirrhOSIS underwent liver transplantation. He experi-enced severe late-phase ACR episodes. o+-----K-----~--__ ~--.. ~~ __ ~~~wK~------+ 0 o 40 Biopsy findings Harvesting injury Mild ACR Severe ACR Postoperative days -ALLOGRAFT REJECTION Case 3 Methylprednisolone 1 g 200 o Biopsy findings Moderate ACR Mlld-modetate ACR Postoperative days restarted. This rejection was confirmed by biopsy subse-quently on POD 13 indicating moderate ACR. TNF-a spikes were observed on POD 4 and 9. TNF-a spike on POD 4 is 1 day before the initiation of augmented antire-jection therapy. Case 5 A 55-year-old man with pancreatic carcinoma and liver metastasis underwent abdominal organ cluster transplanta-tion. The clinical course was complicated by relapsing ACR and subsequent sepsis (Fig 5). In this case. the graft was eventually lost. In the earlier periods (POD 10 and 20). two IL-6 spikes (POD 15 and 19) and one TNF-a spike (POD 700 Case 4 OKT3 10 mgJday - 1m 600 E 500 C, E: '" 400 s:: C-o; u:. 300 Z I-<Ii ~ Methylprednisolone I --0- IL-6 • - TNF .. Ip/Io 'g TB o 10 1 I Biopsy findings Moderate ACR Postoperative days 15 20 Fig 4. A 39-year-old woman With pancreatic somatostatinoma and liver metastasis underwent abdominal organ cluster trans-plantation. She experienced moderate AeR. --0-- IL-6 ____ TNf'.eIph8 TB 40 20 o ACR partially treated CMV hepatitis 1239 Fig 3. A 36-year-old man with alcoholic cirrhosis underwent liver transplantation. He had ex-perienced relapsing ACR epi-sodes. 17) were observed. These elevation of cytokines seem very closely related to serum TB and biopsy tindings (POD 15: moderate ACR, POD 22: mild to moderate ACR, POD 29: moderate ACR). DISCUSSION In this study we have shown that inflammatory cytokines (TNF-a. IL-6) are induced in liver allograft rejection. Daily monitored serum levels of these cytokines are potentially a good premonitor of allograft rejection. Liver allograft rejection is characterized by cellular intil-tration consisting mainly of monocytes/macrophages and activated T Iymphocvtes. Inflammatory cytokines such as TNF-a and IL-6 arc mainly secretcd bv thcse cells. Kuptfcr cells and vascular endothelial cells in the liver may also secrete these cytokines. Therefore. both iniiltrating host immune cells or cells of the allograft (activated Kuptfer cells and endothelial cells) coneeivablv playa role in producing these cytokines.-' In conventional clinical procedures. liver rejection is tirst determined through liver dysfunction. then histologically confirmed hy biopsy, after which antirejection therapy is started. In this study. we observed spike-shaped TNF-n elevation followed hy the elevation of IL-6 (Fig 6). It is well known that TNF-a induces I L-6 secretion, so. theoretically. TNF-n appears earlier in the bloodstream than IL-6. It is also well known that TNF-n is verv ditlicult to detect in thl: blood. The five cases we prl:sented all sutfered from <lggres-,ive rejection. and therefore TNF-n (ould be detected. which is unusual under other circumstances. We attempted to measure TNF-n ill other cases of rejection. but found it impOSSible (data not shown!. TNF-n mav also play an important role in rhe path(1phvs-1240 KITA, IWAKI, DEMETRIS ET AL CaseS 0KT310 mglday Fig 5. A 55-year-old man with pancreatic carcinoma and liver metastasis underwent abdomi-nal organ cluster transplanta-tion. He experienced relapsing ACR episodes 2 weeks after transplantation. and eventually suffered from sepsis and liver graft failure. 200 o 11. . - TN ..... """ T8 Biopsy findings iology of reperfusion injury in liver transplantation. Takei et al4 reported that Kupfer cells were activated following cold preservation, and inflammatory mediators were released from rat liver grafts after reperfusion. Goto et als reported that the release of TNF -a by the rat liver graft depended on the period of preservation. Thus, the activation of Kupfer E 200 C. So .. r; Q. .. ~ 100 j .... <ti d! TNF-alpha spike ____ TNF·.lpha --0- IL-G Anllrelecllon therapy -Liver dysfunction Biopsy (Rejection) Fig 6. Schematic presentation of serum elevation of TNF-" and IL-6 in rejection episodes In liver allograft recipients. Usually. TNF-n and IL -6 spikes appeared prior to liver dysfunction. Clinically. when liver dysfunction appears. liver biopsy IS per-formed. After histological confirmation. antlrejectlon therapy IS Initiated. 10 l! at So .s &J 2 5 :is iii ~ 40 50 Mild-moderate ACR ACR Postoperative days cells plays an important pathophysiological role in graft damage after reperfusion. The present results indicate that inflammatory cytokines such as TNF-a and IL-6 play an important role in the early phase of the rejection episodes. These cytokines are known to upregulate the expression of adhesion molecules such as ICAM-\. thereby facilitating leukocyte adhesion to sinusoi-dal endothelium and subsequently causing graft damage mainlv due to circulatory failure."·7 As we previously noted, the m~re IL-6 spikes demonstrated in recipients. the higher the chance of graft loss.2 Therefore. specific inactivation of cvtokines or of their actions may prove to he a powerful tool i~ the prevention and treatment of allograft rejection and graft failure . REFERENCES I. Imagawa DK. Millis JI\I. Olthotl KM. <:t al: Transplantation 50:21lJ. IlJ'JO 2. Kita Y. lwaki Y. D<:mctris AI. d al: Transplantat""l 57:1037. llJ'J4 ~K Hotlmann MW. \V<lnlg<:tt K. St<:inhotr G. <:t al: Transplanta-tion RR:~OlgK I ')l)3 4. Takci Y. \larzi I. Kaullman Fe. d al: Transplantation 50: 14. 1')t)O .' (J,\lll M. Tak.:i Y. Kawano S . .:t ,iI: lkpat"I'l!.'1' Ih:-IS7. 1'Jl)2 (l. Adams DII. Wang LF. Burn.:tt D. ct al: rr:1I1spianta!lon 50: \h. I()')(I - St':lnlwlr Ci. Iklm:nd :\1. Schrad<:r Il. d .,1 .\111 J 1):lthol 1-I2:-IS I. Il)(), 

Daily serum inflammatory cytokine (tumor necrosis factor-α, interleukin- 6) monitoring in liver transplantation focusing on allograft rejection: A five-case report

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Daily serum inflammatory cytokine (tumor necrosis factor-	, interleukin-6) monitoring in liver transplantation focusing on allograft rejection: a five-case report

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Daily serum inflammatory cytokine (tumor necrosis factor-α, interleukin- 6) monitoring in liver transplantation focusing on allograft rejection: A five-case report

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