Blockade of Lymphocyte Chemotaxis in Visceral Graft-versus-Host Disease

Reshef, Ran; Luger, Selina M.; Hexner, Elizabeth O.; Loren, Alison W.; Frey, Noelle V.; Nasta, Sunita Dwivedy; Goldstein, Steven C.; Stadtmauer, Edward A.; Smith, Jacqueline; Bailey, Susan; Mick, Rosemarie; Heitjan, Daniel F.; Emerson, Stephen G.; Hoxie, James A.; Vonderheide, Robert H.; Porter, David

doi:10.1056/nejmoa1201248

Cited by 235 publications

(213 citation statements)

References 47 publications

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“…Other agents such as vorinostat, a histone deacetylase inhibitor, have demonstrated responses [164]. Maraviroc, a CCR5 chemokine receptor inhibitor, is also being tested [165]. Adaptive transfer of Tregs has also shown to reduce GVHD [166].…”

Section: Future Directionsmentioning

confidence: 99%

State-of-the-art acute and chronic GVHD treatment

Jamil

Mineishi

2015

Int J Hematol

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owing to the advancement in reduced intensity conditioning (RIC) and in patients without HLA-matched donors due to the use of cord blood and haploidentical HSCT [4][5][6]. Although marked improvement has been made in supportive care, immunosuppressive therapy and DNA-based Human Leukocyte Antigen (HLA) typing, graft vs host disease (GVHD) remains a major cause of morbidity and non-relapse mortality among allogeneic HSCT recipients. It was first described by Billingham in 1966 as a syndrome where immunocompetent T cells from the donor recognize and damage the host tissue in an immunocompromised recipient. It presents with heterogeneous symptoms involving multiple organ systems including gastrointestinal tract, skin, mucosa, liver and lungs [7]. In the past clinical features occurring within 100 days after HSCT was called acute GVHD (aGVHD) and those happening after 100 days were labeled chronic GVHD (cGVHD) [8,9]. This definition was rather unsatisfactory thus National Institute of Health (NIH) consensus criteria were developed and have been revised. The criteria have added new categories such as late-onset aGVHD (acute GVHD occurring after 100 days) and overlap syndrome which includes features of both acute and chronic GVHD to the classification, and also have introduced new definitions for organ system involvement [10][11][12]. The categorization of acute vs chronic GVHD is based on the combination of clinical symptoms rather than the time of onset. Depending upon a number of variables associated with patients, donors, and types of transplant, the incidence of aGVHD varies with incidence of grade II-IV GVHD at 40 % in matched related donor (MRD) transplant to 50 % in MUD transplant. The main risk factors for aGVHD include degree of HLA mismatch, age of the patient, previous all immunization of the donor and the kind of GVHD prophylaxis used. About 30-70 % of allogeneic HSCT recipients alive after 100 days will Abstract Graft-versus-host disease (GVHD) remains as the major obstacle for successful hematopoietic stem cell transplant (HSCT). Roughly half of the patients undergoing HSCT develop GVHD which requires treatment, and above 10 % of the patient may die because of it. However, GVHD presents with anti-tumor activity, called graft-versus-tumor (GVT) effect, and it carries significant anti-tumor activity, thus suppressing GVHD completely may increase the relapse of original disease. Thus, it is important to control GVHD to the appropriate level.

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Section: Future Directionsmentioning

confidence: 99%

State-of-the-art acute and chronic GVHD treatment

Jamil

Mineishi

2015

Int J Hematol

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“…32 The first study in patients showed a decreased incidence of visceral injuries when a CCR5-blocking agent was added to aGVHD prophylaxis. 33 Meanwhile, acute cutaneous GVHD still occurred at the expected rates, suggesting that distinct chemokines mediate the homing of effector cells to the skin.…”

Section: Introductionmentioning

confidence: 99%

Diverse T-cell responses characterize the different manifestations of cutaneous graft-versus-host disease

Brüggen

Klein

Greinix³

et al. 2014

Blood

109

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Key Points• Distinct T-cell patterns characterize the acute and chronic forms of cutaneous GVHD.• Increased TSLP expression is an indicator of acute cutaneous GVHD development.Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HCT) and can present in an acute (aGVHD), a chronic lichenoid (clGVHD), and a chronic sclerotic form (csGVHD). It is unclear whether similar or different pathomechanisms lead to these distinct clinical presentations. To address this issue, we collected lesional skin biopsies from aGVHD (n 5 25), clGVHD (n 5 17), and csGVHD (n 5 7) patients as well as serial nonlesional biopsies from HCT recipients (prior to or post-HCT) (n 5 14) and subjected them to phenotypic and functional analyses. Our results revealed striking differences between aGVHD and clGVHD. In aGVHD, we found a clear predominance of T helper (Th)2 cytokines/chemokines and, surprisingly, of interleukin (IL)-22 messenger RNA as well as an increase of IL-22-producing CD4 1 T cells.Thymic stromal lymphopoietin, a cytokine skewing the immune response toward a Th2 direction, was elevated at day 20 to 30 post-HCT in the skin of patients who later developed aGVHD. In sharp contrast to aGVHD, the immune response occurring in clGVHD showed a mixed Th1/Th17 signature with upregulated Th1/Th17 cytokine/chemokine transcripts and elevated numbers of interferon-g-and IL-17-producing CD8

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“…5). Interestingly, both cytokines have previously been shown to be critically involved in allograft rejection, GVHD, and autoimmunity (67)(68)(69)(70)(71)(72)(73)(74).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Protein Geranylgeranylation Specifically Interferes with CD40-Dependent B Cell Activation, Resulting in a Reduced Capacity To Induce T Cell Immunity

Shimabukuro‐Vornhagen

Zoghi

Liebig

et al. 2014

The Journal of Immunology

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Ab-independent effector functions of B cells, such as Ag presentation and cytokine production, have been shown to play an important role in a variety of immune-mediated conditions such as autoimmune diseases, transplant rejection, and graft-versus-host disease. Most current immunosuppressive treatments target T cells, are relatively unspecific, and result in profound immunosuppression that places patients at an increased risk of developing severe infections and cancer. Therapeutic strategies, which interfere with B cell activation, could therefore be a useful addition to the current immunosuppressive armamentarium. Using a transcriptomic approach, we identified upregulation of genes that belong to the mevalonate pathway as a key molecular event following CD40-mediated activation of B cells. Inhibition of 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme of the mevalonate pathway, by lipophilic statins such as simvastatin and atorvastatin resulted in a specific inhibition of B cell activation via CD40 and impaired their ability to act as stimulatory APCs for allospecific T cells. Mechanistically, the inhibitory effect resulted from the inhibition of protein geranylgeranylation subsequent to the depletion of mevalonate, the metabolic precursor for geranylgeranyl. Thus, inhibition of geranylgeranylation either directly through geranylgeranyl transferase inhibitors or indirectly through statins represents a promising therapeutic approach for the treatment of diseases in which Ag presentation by B cells plays a role.

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Blockade of Lymphocyte Chemotaxis in Visceral Graft-versus-Host Disease

Cited by 235 publications

References 47 publications

State-of-the-art acute and chronic GVHD treatment

State-of-the-art acute and chronic GVHD treatment

Diverse T-cell responses characterize the different manifestations of cutaneous graft-versus-host disease

Inhibition of Protein Geranylgeranylation Specifically Interferes with CD40-Dependent B Cell Activation, Resulting in a Reduced Capacity To Induce T Cell Immunity

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