Allosuppressor and allohelper T cells in acute and chronic graft-vs-host disease. V. F1 mice with secondary chronic GVHD contain F1-reactive allohelper but no allosuppressor T cells.

We studied the alloreactive properties of donor T cells obtained from F1 mice that had recovered from the allosuppression of acute graft-vs.-host disease (GVHD) and showed mild symptoms of chronic GVHD, i.e., so-called secondary chronic GVHD. To this end, we used (B10 x DBA/2)F1 mice that had been injected with 10(8) B10 spleen cells 100-150 d previously. Such GVHD F1 mice were repopulated by lympho-hematopoietic cells of donor (B10) origin, which exhibited split tolerance towards the host: Whereas F1-specific donor T helper (Th) cells as well as T cells proliferating in the mixed lymphocyte reaction were readily demonstrable, F1-specific T suppressor (Ts) and T killer (Tk) cells were not, or were hardly, detectable; responses against third-party alloantigens were normal. Upon adoptive transfer to nonirradiated secondary recipients, the B10 cells obtained from the repopulated GVH F1 mice induced F1-specific enlargement of the draining popliteal lymph node and enhancement of the IgG formation therein. B10 cells of the same kind were unable, however, to induce lethal GVHD upon transfer to 950 rad-irradiated secondary (B10 x DBA/2)F1 recipients. We conclude that alloactivated donor Ts/Tk cells disappear from the host at a relatively early stage of GVHD, i.e., at the end of acute GVHD , presumably because they are short-lived. By contrast, the longevity of alloactivated donor Th cells causes the symptoms of secondary chronic GVHD.

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The Role of Selective Depletion of Alloreactive Donor T Cells in Graft-Versus-Host Disease after Allogeneic Bone Marrow Transplantation.

Blood ◽

10.1182/blood.v108.11.5167.5167 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5167-5167

Author(s):

Yihuan Chai ◽

Huiying Qiu ◽

Hui Lv

Keyword(s):

Bone Marrow ◽

T Cells ◽

Graft Versus Host Disease ◽

Acute Gvhd ◽

Allogeneic Bone Marrow ◽

Third Party ◽

Allogeneic Bone ◽

Host Disease ◽

Graft Versus Host ◽

Donor T Cells

Abstract One of the main goals in allogeneic bone marrow(BM) transplantation is the abrogation of graft-versus-host disease (GVHD) with the preservation of antileukemia and antiviral activity. The Study present a selective T cell depletion strategy based on the physical separation of the alloreactive T cells, which were identified by expression of two activation-induced antigens (CD25 and CD69). T cells from C57BL/6(H-2b) mice were first activated with BALB/c (H-2d) recipient spleen cells in a 2-day mixed-lymphocyte-culture (MLC). Following this activation, this compound is selectively depleted based on expression of two activation-induced antigens CD25 and CD69 using magnetic cell sorting. The depleted cells or the untreated cells were then rechallenged respectively in a secondary MLC, with the same stimulator cells or a third-party (DBAH-2k) or tumor- specific (SP2/0, BALB/c-origin myeloma) cells. Cells proliferation were assayed at the indicated time points(1, 2, 3, 4, 5 days). These treated cells or control-cultured cells (2.0×106) mixed with 5.0×106 BM cells from C57BL/6 were transfused respectively by the trail vain into the lethally irradiated BALB/c to observe the survival time, GVHD incidence and pathological analysis. MLC assays demonstrated that this technique led to a significant decrease in alloreactivity of donor cells(29.02~64.17%), which at the same time preserved reactivity against third party cells(49.61~75.69%)and anti-tumor cells(61.14~68.62%). The mice in the group of control-coclutured were died of acute GVHD within 24days. The 7 recipient mice in the treated group were free of acute GVHD, and 3 mice were died of acute GVHD (aGVHD) within 23 days. MACS-based ex-vivo depletion of alloreactive donor T cells based on expression of two activation-induced antigens (CD25 and CD69) could inhibit anti-host responses, by contrast, anti-SP2/O and anti-third-party responses were preserved. Cotransplantation of these selected depleted cells and BM cells could reduce aGVHD.

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In Allogeneic Transplant Recipients Th17 Cells Originate From Donor Stem Cells and Reside In Target Organs of Chronic Graft-Versus-Host Disease

Blood ◽

10.1182/blood.v122.21.5425.5425 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5425-5425

Author(s):

Antonia MS Mueller ◽

Mareike Florek ◽

Natascha J Kuepper ◽

Jessica Poyser ◽

Judith A. Shizuru

Keyword(s):

T Cells ◽

T Cell ◽

Th17 Cells ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Cell Infiltration ◽

Host Disease ◽

T Cell Infiltration ◽

Target Organs ◽

Donor T Cells

Abstract Graft-vs-host disease (GVHD) remains a major complication of allogeneic hematopoietic cell transplantation (HCT). Acute GVHD results from activated donor T cells that infiltrate and damage target organs, producing an inflammatory state. In contrast, the pathophysiology of chronic graft-vs-host disease (cGVHD) remains poorly understood. cGVHD can follow acute GVHD or emerge de novo (>d+100). The clinical picture varies and manifestations can resemble autoimmune disorders. Because IL-17 has emerged as a principal cytokine involved in autoimmunity, Th17 cells have attracted much attention in the transplant community. While IFNg-producing Th1 cells appear to drive acute GVHD, the role of Th17 cells in the pathophysiology of GVHD has not been fully clarified. Here, we used an established minor-antigen disparate mouse model of acute and chronic GVHD to examine the emergence of IL-17+CD4+ Th17 cells post-HCT. Lethally irradiated BALB.B mice received pure hematopoietic stem cells (HSC; cKIT+Thy1.1loSca1+Lin-) or HSC plus splenic T cells from C57BL/6 donors (HSC: GFP; TC: CD45.1+). At several time points lymphoid and GVHD target organs were analyzed for donor T cell infiltration and T cell IL-17 expression. In this model recipients of HSC + T cells developed acute GVHD with intestinal involvement (diarrhea, weight loss) and a mortality of ∼30%, while mice given pure HSC remained healthy. Survivors stabilized around d45, but developed clinically evident chronic GVHD after 6-12 mo manifested by sclerodermatous skin excoriations and liver fibrosis/cirrhosis. Donor T cell infiltration of tissues (spleen, lymph nodes (LN), liver, intestines) was high at 2 and 4 wks post-HCT, but there was no detectable IL-17 production by CD4 cells during acute GVHD. The degree of donor T cell infiltration decreased (as acute GVHD improved) in these tissues. However, at 2 mo post-HCT higher percentages CD4+IL-17+ cells were observed, first in intestines and mesenteric LN, followed by liver and skin. At all time points post-HCT proportions of Th17 cells were higher in HCT recipients (of HSC +/- T cells) as compared to normal wild-type (WT) tissues. To summarize, our key findings are: (i) In our model acute GVHD was driven by adoptively transferred mature (CD4+) T cells that acquired a Th1 phenotype, whereas IL-17 producing donor cells were not detectable during this period. IFNg and T-bet are negative regulators of RORgT, the master regulator of Th17. Thus, this observation is consistent with the idea that in the presence of donor Th1 cells the development of Th17 cells is suppressed. (ii) The effect of Th1-related suppression of Th17 persisted beyond the acute phase: recipients of T-cell replete grafts that survived acute GVHD but later developed chronic GVHD did not demonstrate increased CD4+IL-17+ cells. In these mice, organ-infiltrating donor T cells were primarily adoptively transferred T cells, supporting the postulation that no plasticity exists between committed Th1 and Th17 cells. (iii) Signs of chronic GVHD were observed in animals that had not suffered from severe acute GVHD. In particular, in groups without acute GVHD we observed CD4+IL-17+ cells starting at 2 mo, peaking around 6 mo and which stabilized >1 yr post-HCT. In spleen and peripheral LN of these mice only low levels of CD4+IL-17+ cells were detectable, but their proportion was high in GVHD target organs (liver, intestines, skin). The susceptibility of organs appeared to change post-HCT with high proportions of CD4+IL-17+ cells in the intestines at 2 mo post-HCT that decreased over time. In contrast, CD4+IL-17+ cells in the liver increased later in the time course (Figures). (iv) A centrally important observation was that CD4+IL-17+ cells primarily originated from donor HSC, even in recipients of mature donor T cells. Likewise, recipients of pure HSC showed increasing proportions of Th17 cells over time, and could also manifest signs of cGVHD. From our model we conclude that IL-17 does not contribute to acute inflammatory GVHD. However, IL-17 can be involved in an alternative pathophysiologic mode of chronic GVHD development in the absence of acute inflammation. Since CD4+IL-17+ cells derive from donor HSC and undergo maturation in the host this form of GVHD is delayed, and the emergence and activity of these cells appears to constitute a true autoimmune phenomenon. Our novel hypothesis may explain parts of the complex and obscure pathophysiology of chronic GVHD. Disclosures: No relevant conflicts of interest to declare.

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Distinct Roles for Donor and Host Antigen Presenting Cells and Costimulatory Molecules in Murine Chronic Graft-Vs-Host Disease: Requirements Depend on Target Organ.

Blood ◽

10.1182/blood.v104.11.3059.3059 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3059-3059

Author(s):

Britt Anderson ◽

Jennifer McNiff ◽

Dhanpat Jain ◽

Bruce R. Blazar ◽

Warren D. Shlomchik ◽

...

Keyword(s):

Acute Gvhd ◽

Chronic Gvhd ◽

Antigen Presenting Cells ◽

Costimulatory Molecules ◽

Cd4 Cells ◽

Host Disease ◽

Graft Vs Host Disease ◽

Donor T Cells ◽

Antigen Presenting

Abstract The application of allogeneic stem cell transplantation is limited by graft-vs.-host disease (GVHD). GVHD can be divided into acute and chronic forms that likely have different initiation requirements and pathogenic mechanisms. Previously we demonstrated that residual host antigen presenting cells (APC) were required for CD8-mediated acute GVHD (aGVHD). In contrast, here we show that either donor or host APCs can initiate CD4-mediated GVHD in the B10.D2(H-2d)→BALB/c (H-2d) model of chronic GVHD (cGVHD). We selectively impaired donor APCs, host APCs or both by using donors and/or hosts deficient in both costimulatory molecules CD80 and CD86 (CD80/86−/−). When all CD28:CD80/86 signaling was prevented by using CD80/86−/− donors and hosts, wild type (WT) CD4 cells were unable to induce cGVHD. Therefore donor CD4 cells absolutely require signals from CD80/86 to mediate cGVHD. Next we compared cGVHD in CD80/86−/− BM + CD4→WT vs. WT BM + CD4→CD80/86−/− hosts, to debilitate antigen presentation by donor or host APCs, respectively. Cutaneous cGVHD developed in both groups, demonstrating that donor or recipient APCs are sufficient to initiate disease. However, the incidence of cutaneous cGVHD in CD80/86−/− recipients was less than that in WT→WT recipients (P<0.01), suggesting that recipient APCs are more important than donor APCs for skin cGVHD. In support of this, cGVHD was not reduced inCD80/86−/− BM + CD4 →WT recipients. Therefore, reconstitution with defective donor APCs does not affect disease when host APCs are intact. To address whether host APCs were dispensable, we compared cGVHD in donor→host (APCs >98% donor) and host→host chimeric recipients. Similar cGVHD developed in both chimeras; thus donor APCs alone are sufficient, consistent with the data in CD80/86−/− hosts. Interestingly, cGVHD was initiated in the absence of significant host hematopoietic antigen. Thus, exogenously acquired parenchymal antigen was sufficient. The above experiments focused on cutaneous GVHD. However, recipients of WT BM versus non-WT BM consistently developed diarrhea and increased weight loss. While CD4 recipients of CD80/86−/− or CD40−/− BM regained and maintained their original weights, CD4 recipients of WT BM never returned to their pre-transplant weight (P<0.01 after day 15). Consistent with the clinical finding, recipients of CD4 cells and WT BM had higher bowel pathology scores than equivalent mice that received CD80/86−/− BM (P<0.01). Recipients of CD80/86−/− BM + WT CD4 cells had statistically indistinguishable path scores from recipients of either type of BM without CD4 cells (P=0.19 and 0.73); therefore, without CD80/86 expression on donor BM, there was no statistical evidence that donor T cells caused bowel GVHD. These results provide new insights into the role of donor APCs in GVHD and demonstrate that APC requirements differ depending on the site of disease, both novel findings. They also identify differences in APC requirements between CD8-mediated aGVHD and CD4-mediated cGVHD and further highlight APCs as additional targets for GVHD prevention and therapy.

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Prevention of Graft-Versus-Host Disease by Selective Depletion of Alloreactive T Cells.

Blood ◽

10.1182/blood.v108.11.3174.3174 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3174-3174

Author(s):

NgocDiep Le ◽

Nelson Chao

Keyword(s):

T Cells ◽

Graft Versus Host Disease ◽

Third Party ◽

Dependent Manner ◽

Activated T Cells ◽

Host Disease ◽

Graft Versus Host ◽

Viral Antigens ◽

Alloreactive T Cells ◽

Donor T Cells

Abstract OBJECTIVE: Mismatched allogeneic hematopoietic cell transplantation (alloHCT) carries a high risk of life-threatening graft-versus-host disease (GVHD) due to activation of donor T cells by antigens present on host cells. Removal of donor mature T cells can prevent GVHD but leads to an increased incidence of opportunistic infections and disease relapse. This study aims to selectively deplete host-reactive donor T cells responsible for GVHD while preserving T cells with anti-tumor and anti-viral effects. METHODS: We utilized a photosensitizer, 4,5-dibromorhodamine-methyl ester (TH9402, Celmed Biosciences Inc., Saint-Laurent, Canada), in an ex vivo photodynamic purging (PDP) process to specifically eradicate host-reactive T cells. Donor T cells with anti-host specificity were identified in a unidirectional mixed lymphocyte culture (MLC) where they were activated and became proliferating. TH9402 is taken up by all cells and extruded out of the cell by P-glycoprotein (Pgp) in non-activated cells. However, due to inactivation of Pgp in activated T cells, TH9402 is retained in the mitochondria. Upon exposure to 514 nm light in the Theralux™ device (Celmed), it becomes extremely cytotoxic resulting in cell death. In this study, after treatment with various concentrations of TH9402, the cells were exposed to light for the elimination of alloreactive T cells. The efficiency of allodepletion was assessed by Granzyme B (GrB) assay. T-cell proliferation assays were used to demonstrate the preservation of anti-tumor and anti-viral effects. Finally, the skin explant assay, an in vitro model of GVHD, was utilized to examine the efficacy of the PDP treatment in the removal of alloreactive T cells responsible for GVHD. The parameters of the PDP treatment were optimized for use in subsequent clinical studies. RESULTS: After 72-hour MLC, optimal proliferative response was obtained at a responder: stimulator ratio of 1:1. Activated T cells expressed high level of activation markers such as CD25 and CD69. After the PDP treatment with 20μM of TH9402, alloreactive T cells were consistently depleted by more than 2 logs (Figure 1). Moreover, the PDP treatment did not significantly affect anti-tumor and anti-viral effects as evidenced by responses to third-party stimulators (Figure 2A), cytomegalovirus (CMV) (Figure 2B) and Candida antigens. Most importantly, co-culture of recipient’s skin with PDP-treated cells showed a reduction of graft-versus-host reaction (GVHR) in a TH9402-dose dependent manner. The PDP treatment with 20μM of TH9402 completely abolished GVHR in a skin explant assay. CONCLUSIONS: The PDP treatment can effectively remove donor T cells responsible for GVHD while preserve T cells with anti-tumor and anti-viral effects. These preclinical results provide a basis for initiating a clinical trial to assess the feasibility and efficacy of infusing PDP-treated donor T cells to alloHCT recipient in order to augment anti-tumor and anti-pathogen effects without causing GVHD. Figure 1 PDP treatment reduceds the frequency of alloreactive T cells in a TH9402 does dependent manner. Figure 1. PDP treatment reduceds the frequency of alloreactive T cells in a TH9402 does dependent manner. Figure 2 PDP treatment preserves responses to third-party stimulator and viral antigens. Figure 2. PDP treatment preserves responses to third-party stimulator and viral antigens.

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Genetic Variations in Heparanase Gene (HPSE) Are Associated with Increased Risk of Graft Vs. Host Disease Following Allogeneic Hematopoietic Stem Cell Transplantation: Effect of Discrepancy Between Recipient and Donor.

Blood ◽

10.1182/blood.v114.22.3556.3556 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3556-3556

Author(s):

Olga Ostrovsky ◽

Avichai Shimoni ◽

Israel Vlodavsky ◽

Arnon Nagler

Keyword(s):

T Cells ◽

Heparan Sulfate ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Independent Effect ◽

Host Disease ◽

Expression Levels ◽

Donor T Cells ◽

Grade Ii ◽

Donor Genotype

Abstract Abstract 3556 Poster Board III-493 Introduction Graft-versus-host disease (GVHD) is the most common cause of overall mortality and morbidity after HSCT. Heparanase, endo-â-glucuronidase that specifically cleaves the saccharide chains of heparan sulfate proteoglycans, is involved in the process of inflammation and release of heparan sulfate-bound chemokines, cytokines and bioactive angiogenic factors that are main players in the development of GVHD. Therefore, we investigated the possible association of HPSE gene SNPs with the risk of post HSCT GVHD and transplantation outcome. Patients and methods Four hundred and fourteen patients with hematological malignancies and their HLA matched donors were included in the study. Genotyping of two HPSE gene SNPs rs4693608 and rs4364254 was carried out using PCR-RFLP-based analysis and allele-specific amplification. Results Assessment of heparanase gene SNPs among healthy individuals demonstrated a significant correlation between HPSE gene SNPs and the expression level of heparanase, SNP rs4693608 being the most prominent (p=0.00043). This approach allowed distribution of all possible HPSE genotype combinations into three groups (LR, MR and HR) correlating with low, intermediate and high heparanase mRNA and protein expression levels. In the group of HSCT patients we found a highly significant correlation between HPSE gene SNPs rs4693608 and rs4364254, their combinations and risk of acute GVHD. The cumulative incidence of acute GVHD, grade II-IV, was 54.4% (95% CI 44.7-66.2) in the recipient group HR, while in recipient groups MR and LR, the cumulative incidences were 40.5% (95% CI 33.2-49.4) and 24.9% (95%CI 17.7-34.9), respectively (P=0.0001). Moreover, discrepancy between recipient and donor in these SNPs combinations significantly affected the risk of acute GVHD. Genotype combination LR in patients exerted a protective effect against GVHD regardless of the donor genotype combinations. Acute GVHD rates were highest when recipients possessed genotype combinations HR. correlating with high heparanase mRNA levels, while their donors possessed the MR or LR genotype combinations correlating with a lower heparanase mRNA level, (HR-MR and HR-LR pairs). The other combinations were associated with an intermediate risk. Therefore, we divided all recipient-donor pairs to three groups according to potential risk for acute GVHD development. The first group, LAGR, included three pairs with low risk of acute GVHD development (LR-LR, LR-MR, and LR-HR pairs). The second cohort, HAGR, contained pairs with high risk of acute GVHD development (HR-MR and HR-LR pairs). The third group, MAGR, consisted of pairs with moderate risk of acute GVHD development (MR-MR, MR-HR, MR-LR and HR-HR pairs). Cumulative rate of acute GVHD incidence was 71.2% (95% CI 58.2-87.0) in the HAGR group, 41.5% (95% CI 34.4-50.1) in the MAGR group, and 24.9% (CI 95% 17.7-34.9) in the LAGR group (÷2=29.3, P< 0.00001 for grade II-IV and ÷2=34.1, P< 0.00001 for grade III-IV). In addition, HPSE gene SNPs disclosed a correlation with extensive chronic GVHD, non-relapse mortality and overall survival. Multivariate analysis confirmed the independent effect of both host genotype and host-donor genotype risk groups. Conclusions The study demonstrated significant correlation between HPSE gene SNPs and heparanase expression levels and the risk of acute and extensive chronic GVHD. Our findings may imply the involvement of heparanase in the pathogenesis of GVHD. We speculate that secreted levels of cytokines and chemokines affected by heparanase are higher in patients possessing HR genotype in comparison to possessors of the MR and LR genotypes. Higher cytokine and chemokine signals originating from the patient activate donor T-cells and increase the risk of GVHD. When donor T-cells originated from a donor environment with lower heparanase levels as dictated by donor genotype LR/MR, the infusion into a high heparanase level environment may cause hyperactivation and an even higher risk of GVHD. This aggressive phenotype of donor T lymphocytes results in infiltration and destruction of patient tissues and GVHD development. Disclosures: No relevant conflicts of interest to declare.

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Combined Th2 cytokine deficiency in donor T cells aggravates experimental acute graft-vs-host disease

Experimental Hematology ◽

10.1016/j.exphem.2008.02.010 ◽

2008 ◽

Vol 36 (8) ◽

pp. 988-996 ◽

Cited By ~ 41

Author(s):

Isao Tawara ◽

Yoshinobu Maeda ◽

Yaping Sun ◽

Kathleen P. Lowler ◽

Chen Liu ◽

...

Keyword(s):

T Cells ◽

Host Disease ◽

Th2 Cytokine ◽

Graft Vs Host Disease ◽

Donor T Cells ◽

Acute Graft

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Allosuppressor and allohelper T cells in acute and chronic graft-vs-host disease. I. Alloreactive suppressor cells rather than killer T cells appear to be the decisive effector cells in lethal graft-vs.-host disease.

Journal of Experimental Medicine ◽

10.1084/jem.155.5.1501 ◽

1982 ◽

Vol 155 (5) ◽

pp. 1501-1522 ◽

Cited By ~ 50

Author(s):

A G Rolink ◽

T Radaszkiewicz ◽

S T Pals ◽

W G van der Meer ◽

E Gleichmann

Keyword(s):

T Cells ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Suppressor Cells ◽

Activated T Cells ◽

Killer Cells ◽

Host Disease ◽

Effector Cells ◽

Graft Vs Host Disease ◽

T Killer Cells

Splenic T cells from B10 donors were injected into irradiated (B10 x DBA/2)F1 mice. Either 5 or 6 d later, activated donor T cells were recovered from the spleens of these primary F1 (1 degree F1) recipients and transferred to groups of nonirradiated syngeneic F1 (2 degrees F1) recipients. Whereas day-5-activated parental T cells induced the characteristic symptoms of acute graft-vs.-host disease (GVHD) and eventually lethal GVHD, day-6-activated B10 T cells failed to induce acute GVHD but induced symptoms of chronic GVHD. Interestingly, the inability of day-6-activated T cells to induce lethal GVHD could not be ascribed to a lack in anti-F1 T killer cells. The combined results of functional studies indicated that day-6 cells were enriched for alloreactive helper T cells, whereas day-5 cells were enriched for alloreactive suppressor cells. Hence, our findings indicate that acute GVHD and lethal GVHD are caused by alloreactive donor T suppressor but not T killer cells, and that symptoms of chronic GVHD are caused by alloreactive donor T helper cells.

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SOCS3 regulates graft-versus-host disease

Blood ◽

10.1182/blood-2009-12-259598 ◽

2010 ◽

Vol 116 (2) ◽

pp. 287-296 ◽

Cited By ~ 25

Author(s):

Geoffrey R. Hill ◽

Rachel D. Kuns ◽

Neil C. Raffelt ◽

Alistair L. J. Don ◽

Stuart D. Olver ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Graft Versus Host Disease ◽

Acute Gvhd ◽

Transforming Growth Factor ◽

Chronic Gvhd ◽

Cytokine Signaling ◽

Host Disease ◽

Graft Versus Host ◽

Donor T Cells

Abstract Suppressor of cytokine signaling-3 (SOCS3) is the main intracellular regulator of signaling by granulocyte colony-stimulating factor, an immune-modulatory cytokine used to mobilize stem cells for transplantation. We have therefore studied the contribution of SOCS3 to the spectrum of graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (SCT). Grafts from SOCS3−/Δvav donor mice in which SOCS3 deficiency is restricted to the hematopoietic compartment had an augmented capacity to induce acute GVHD. With the use of SOCS3−/ΔLysM and SOCS3−/Δlck donors in which SOCS3 deficiency was restricted to the myeloid or T-cell lineage, respectively, we confirmed SOCS3 deficiency promoted acute GVHD mortality and histopathology within the gastrointestinal tract by effects solely within the donor T cell. SOCS3−/Δlck donor T cells underwent enhanced alloantigen-dependent proliferation and generation of interleukin-10 (IL-10), IL-17, and interferon-γ (IFNγ) after SCT. The enhanced capacity of the SOCS3−/Δlck donor T cell to induce acute GVHD was dependent on IFNγ but independent of IL-10 or IL-17. Surprisingly, SOCS3−/Δlck donor T cells also induced severe, transforming growth factor β– and IFNγ-dependent, sclerodermatous GVHD. Thus, the delivery of small molecule SOCS3 mimetics may prove to be useful for the inhibition of both acute and chronic GVHD.

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