Febbraio MA, Pedersen BK .2005.

"Contraction-induced myokine production and

release: is skeletal muscle an endocrine organ?". Exerc Sport Sci Rev 33 (3): 114–
119.
Banks WA, Kastin AJ, Gutierrez EG .1994. "Penetration of interleukin-6 across the
murine blood–brain barrier". Neurosci. Lett. 179 (1–2): 53–6.
Bastard J, Jardel C, Delattre J, Hainque B et al. 1999. "Evidence for a Link
Between Adipose Tissue Interleukin-6 Content and Serum C-Reactive Protein
Concentrations in Obese Subjects". Circulation 99 (16): 2219–2222.

Eric G. Lee, Lerin R. Luckett-Chastain, Kaitlin N. Calhoun, Benjamin Frempah,

Anja Bastian, and Randle M. Gallucci (2019) , Interleukin 6 Function in the Skin
and Isolated Keratinocytes Is Modulated by Hyperglycemia, Journal of
Immunology Research : 9
Article ID 5087847, 9 pages
https://doi.org/10.1155/2019/5087847

Zelenika D, Adams E, Humm S, et al. The role of CD4 T-cell subsets in

determining transplantation rejection or tolerance. Immunol Rev 2001; 182: 164.

Murphy, S. P., Porrett, P. M. & Turka, L. A. Innate immunity in transplant

tolerance and rejection. Immunol Rev 241, 39–48, https://doi.org/10.1111/j.1600-
065X.2011.01009.x (2011).
Calota, D. R., Nitescu, C., Florescu, I. P. & Lascar, I. Surgical management of
extensive burns treatment using allografts. J Med Life 5, 486–490 (2012).
Solhjou, Z. et al. Novel Application of Localized Nanodelivery of Anti-
Interleukin-6 Protects Organ Transplant From Ischemia-Reperfusion Injuries. Am J
Transplant 17, 2326–2337, https://doi.org/10.1111/ajt.14266 (2017).
Ford HR, Hoffman RA, Tweardy DJ, et al. Evidence that production of interleukin 6 within
the rejecting allograft coincides with cytotoxic T lymphocyte development. Transplantation
1991; 51: 656.
Benghiat FS, Graca L, Braun MY, et al. Critical influence of natural regulatory CD25_ T
cells on the fate of allografts in the absence of immunosuppression. Transplantation 2005;
79: 648.
CD4+ T-cells are divided into two types: Th1 and Th2 cells. Th1 cells mainly secrete IL-2,
IFN-γ, TNF and GM-CSF, while Th2 cells mainly secrete IL-4, IL-5, IL-6, IL-10 and IL-13.
Previous studies have shown that Th1-type cytokines inhibit the expression of Th2-type
cytokines, and vice versa. Our results revealed that when immune tolerance occurred in
grafted skin, Th2-type cytokine (IL-4, IL-10) expression increased and Th1-type cytokine
(IFN-γ) expression decreased. Therefore, we speculate that changes in Th1- and Th2-type
cytokine expression are important in the process of immune tolerance in grafted skin
Ming-MinWangaYu-LinYangbJian-JunSuncXiang-DongLid , 2018, Induction of immune
tolerance and altered cytokine expression in skin transplantation recipients
Volume 34, Issue 6, June 2018, Pages 330-334 scincedirect
Ming MinWang, Yu-LinYang, Jian-JunSun, Xiang-DongLi (2018) Induction of immune
tolerance and altered cytokine expression in skin transplantation recipients, sciencedirect ,
34 : 330-334
The low levels of IL-1 and TNF may be important f actors to lighten the intensity of local
rejection in the intermingled skin graft. The temporarily peaked IL-6 is both an inducer which
induces the production of local IL-1 receptor antagonists and soluble TNF receptors and a
signal which indicates a local enhancement of Th(2) cells. The mild rejection process and th e
synchronized cytokine level during the later phases suggest a possible chimerism between the
mals and the maus.
Wu J, et al. (2001). Dynamic changes of interleukin-1, interleukin-6 and tumor necrosis
factor in intermingled skin graft in burned rats, Chin J Traumatol 24 (2)
Ellis J.D. ,  Neil D.A.,  Inston N.G. ,  Jenkinson E., M.T. Drayson, P. Hampson, et al. (2016).
Inhibition of histone deacetylase 6 reveals a potent immunosuppressant effect in models of
transplantation, Transplantation:  100 (2016), pp. 1667-1674

the use of skin allografts represents a lifesaving strategy for severe burn patients, but their
ultimate rejection limits their potential efficacy and utility. IL-6 is a major pleiotropic
cytokine which critically links innate and adaptive immune responses.

we devised anti-IL-6 receptor eluting gelatin methacryloyl (GelMA) biomaterials

(GelMA/anti-IL-6), which were implanted at the interface between the wound beds and skin
allografts. Our visible light crosslinked GelMA/anti-IL-6 immunomodulatory biomaterial
(IMB) demonstrated a stable kinetic release profile of anti-IL-6. In addition, the incorporation
of anti-IL-6 within the GelMA hydrogel had no effect on the mechanical properties of the
hydrogels. Using a highly stringent skin transplant model, the GelMA/anti-IL-6 IMB almost
doubled the survival of skin allografts. The use of GelMA/anti-IL-6 IMB was far superior to
systemic anti-IL-6 receptor treatment in prolonging skin allograft survival. As compared to
the untreated control group, skin from the GelMA/anti-IL-6 IMB group contained
significantly fewer alloreactive T cells and macrophages.
We synthesized an immunomodulatory biomaterial (IMB), which is a photocrosslinkable
GelMA hydrogel that contains anti-IL-6 receptor (referred to as  GelMA/anti-IL-6) and can
be crosslinked in vivo using visible light (Fig. 1A). We tested different concentrations of
GelMA hydrogels for various in vitro and in vivo studies in our previous work35 and we
found that lower concentration of GelMA (e.g. 5%) can enhance tissue ingrowth and
vascularization
Intra-graft inflammatory responses have increasingly received attention as an instigator of the
alloimmune response15,16,17,18,19. An increase in immunostimulatory cytokines results in a
pro-inflammatory milieu that tips the balance in favor of effector immune responses, as
opposed to regulatory immune responses20,21. A key inflammatory cytokine that is
recognized increasingly for its role in linking innate inflammatory immune activity to the
augmentation of alloimmune responses is IL-6. IL-6 is a major pleiotropic inflammatory
cytokine increases markedly in the circulation and at the site of the wound22,23,24. Higher
IL-6 levels have also been associated with poorer outcomes in burn patients25,26,27.
We and others have shown that ischemic dendritic cells (DCs) produce a large amount of IL-
6, a key inflammatory cytokine that downregulates regulatory T cells (Tregs) while
potentiating alloreactive CD4+ T cells28,29,30,31,32. Altogether, accumulating experimental
data now highlight the importance of innovative strategies that target intra-graft inflammation
and innate immunity to improve transplant outcomes33.
mice that received intravenous injections of anti-IL-6 (100 μg/mouse, daily from days 0–3
and every other day until day 11; total of 800 μg of anti-IL-6), and a GelMA/anti-IL-6 (100 
μg/GelMA)-implanted group (n = 5 mice/group). Twelve days post-skin transplantation, most
of the skin allografts in the control group shrank markedly and were rejected 
Uehara, M., Li, X., Sheikhi, A. et al. Anti-IL-6 eluting immunomodulatory biomaterials
prolong skin allograft survival. Sci Rep 9, 6535 (2019) doi:10.1038/s41598-019-42349-w
Nicolas Granofszky1, Andreas M. Farkas1, Moritz Muckenhuber1, Benedikt Mahr1, Lukas
Unger1, Svenja Maschke1, Nina Pilat1, Anti-Interleukin-6 Promotes Allogeneic Bone
Marrow Engraftment and Prolonged Graft Survival in an Irradiation-Free Murine
Transplant Model, Front. Immunol., 19 July 2017

Hur, J. et al. Inflammatory cytokines and their prognostic ability in cases of major
burn injury. Ann Lab Med 35, 105–
110, https://doi.org/10.3343/alm.2015.35.1.105 (2015).

IL-6 and TNF-α synergistically impair the efficacy of therapies that promote allograft
acceptance.
Our previous work demonstrated that DCs produce both IL-6 and TNF-α during acute
allograft rejection

We next performed experiments to examine the role of either IL-6 or TNF-α on the T cell
alloimmune-promoting effects of the conditioned medium in our in vitro culture system.
Treatment of T cells with either an inhibitory anti–IL-6 mAb or an anti–TNF-α mAb reduced
T cell responses during allostimulation (Figure 2, A and B)
Shen Hua and Goldstein Daniel R (2009). IL-6 and TNF-α Synergistically Inhibit Allograft
Acceptance, JASN, 20 (5) 1032-1040; DOI: https://doi.org/10.1681/ASN.2008070778
Samoilova EB, Horton JL, Hilliard B, Liu, T-ST, Chen Y: IL-6-deficient mice are resistant to
experimental autoimmune encephalomyelitis: Roles of IL-6 in the activation and
differentiation of autoreactive T cells. J Immunol 161 : 6480– 6486, 1998

Kelso A (1994). The enigma of cytokine redundancy. Immunol Cell Biol 72 : 97– 101, 1994

↵
Hata H, Sakaguchi N, Yoshitomi H, Iwakura Y, Sekikawa K, Azuma Y, Kanai C, Moriizumi
E, Nomura T, Nakamura T, Sakaguchi S: Distinct contribution of IL-6, TNF-alpha, IL-1, and
IL-10 to T cell-mediated spontaneous autoimmune arthritis in mice. J Clin Invest 114 : 582–
588, 2004

Batal, I. et al. The mechanisms of up-regulation of dendritic cell activity by

oxidative stress. J Leukoc Biol 96, 283–293, doi:jlb.3A0113-033RR (2014).

Inflammation Biomarkers and Correlation to Wound Status After Full-Thickness Skin

Grafting
Karim Saleh1*, Ann-Charlotte Strömdahl1, Kristian Riesbeck2 and Artur Schmidtchen1,3
Front. Med., 12 July 2019 | https://doi.org/10.3389/fmed.2019.00159

Whether cytokines are also elevated in the skin graft at the protein level remains to be
confirmed, but some of the cytokines identified, such as IL-6, are known to enhance T cell
proliferation [(13) and our in vitro results], suggesting that they may enhance the effector
function
of alloreactive T cells when they enter the skin graft
Skin-restricted commensal colonization
accelerates skin graft rejection
Lei Yuk Man, Yasmine Belkaid, Maria-Luisa Alegre
JCI Insight. 2019.
Penggunaan skin allografts merupakan strategi yang dapat menyelamatkan nyawa pasien luka
bakar parah, tapi reaksi penolakan yang terjadi dapat membatasi kemanjuran dan efikasi dari
skin allografts itu (Calota et al., 2012). IL-6 adalah sitokin pleiotropik utama yang
menghubungkan respon imun bawaan dan adaptif (Uehara et al., 2019; Nicolas et al.,2017).
IL-6, diketahui meningkatkan sel T proliferasi, menunjukkan bahwa IL-6 dapat
meningkatkan fungsi efektor sel T alloreaktif ketika memasuki cangkok kulit (Lei et al.,
2019; Benghiat et al. 2005).

Peningkatan sitokin imunostimulatori menghasilkan lingkungan pro-inflamasi yang memberi

keseimbangan pada respon imun efektor, yang berlawanan dengan respons imun regulatori.
Sitokin inflamasi kunci yang semakin dikenal karena perannya dalam menghubungkan
aktivitas imun inflamasi bawaan dengan augmentasi respons alloimun adalah IL-6. IL-6
adalah sitokin inflamasi pleiotropik utama yang meningkat secara nyata dalam sirkulasi dan
di lokasi luka. Tingkat IL-6 yang lebih tinggi juga telah dikaitkan dengan hasil yang lebih
buruk pada pasien luka bakar (Uehara et al., 2019; Hur et al., 2015)

IL-6 dan TNF-α secara sinergis menganggu efikasi terapi yang mendukung penerimaan
allograft (Eric et al., 2019. Penelitian sebelumnya menunjukkan bahwa Dendritic Cell (DC)
menghasilkan IL-6 dan TNF-α selama penolakan allograft akut (Balta et al., 2014; Shen dan
Goldstein, 2009; Hata et al., 2004; Samoilova et al., 1998, Kelso et al., 1994)
Sel T CD4 + dibagi menjadi dua jenis: sel Th1 dan Th2. Sel-sel Th1 terutama mengeluarkan
IL-2, IFN-γ, TNF dan GM-CSF, sedangkan sel-sel Th2 terutama mensekresi IL-4, IL-5, IL-6,
IL-10 dan IL-13. Penelitian sebelumnya telah menunjukkan bahwa sitokin tipe Th1
menghambat ekspresi sitokin tipe Th2, dan sebaliknya (Karim et al., 2019). Pada penelitian
(Minwang, 2018) mengungkapkan bahwa ketika reaksi penolakan terjadi pada kulit yang
dicangkokkan, ekspresi sitokin tipe-Th2 (IL-4, IL-6, IL-10) meningkat dan ekspresi sitokin
tipe-Th1 (IFN-γ) menurun (Murphy et al., 2011). Oleh karena itu, peneliti berspekulasi
bahwa perubahan ekspresi sitokin tipe Th1 dan Th2 penting dalam proses toleransi imun pada
kulit yang dicangkokkan (Ellis et al., 2018; Wu et al., 2001).

Penjelasan mekanisme yang mungkin adalah bahwa graft yang memproduksi IL-6
menyebabkan aktivasi perifer Sel T menghasilkan peningkatan produksi IFN oleh CD8 dan
peningkatan proliferasi sel T CD4 (Zelenika et al., 2001). Laporan terbaru menunjukkan
bahwa ekspresi IL-6 dapat mengatasi supresi imun yang dimediasi oleh sel-sel TReg dengan
aktivasi langsung sel T. Hasil ini mendukung hipotesis bahwa defisiensi IL-6 memperpanjang
kelangsungan hidup graft yang karena gagalnya pengaktifan Sel T dengan adanya penekanan
imun dimediasi oleh sel Treg (Yurong et al., 2007; Ford et al., 1991).
Yurong Liang,1,5 Kenneth Christopher,2 Patricia W. Finn,1 Yolonda L. Colson,3 and David
L. Perkins1,4,6 Graft Produced Interleukin-6 Functions as a Danger
Signal and Promotes Rejection After Transplantation Transplantation 2007;84: 771–777)
Pada penelitian Uehara et al., 2019 dirancang sebuah biomaterial gelatin methacryloyl
(GelMA) yang mengandung anti-IL-6 reseptor (GelMA / anti-IL-6), yang ditanamkan pada
permukaan antara lapisan luka dan allograft kulit. Menggunakan model transplantasi kulit
yang sangat ketat, GelMA / anti-IL-6 dapat melipatgandakan kelangsungan hidup allografts
kulit. Penggunaan GelMA / anti-IL-6 IMB jauh lebih unggul daripada pengobatan reseptor
anti-IL-6 sistemik dalam memperpanjang kelangsungan hidup allograft kulit. Dibandingkan
dengan kelompok kontrol yang tidak diobati, kulit dari kelompok IMMA GelMA / anti-IL-6
mengandung lebih sedikit sel T alloreactive dan makrofag. Skin allograft pada kelompok
GelMA / anti-IL-6 tampak lebih sehat daripada graft pada tikus yang diobati secara sistemik
dengan anti-IL-6 ( Solhjou et al., 2017)