Biology of Blood and Marrow Transplantation
Volume 15, Issue 1, Supplement , Pages e1-e7, January 2009

Genomic and Proteomic Analysis of Allogeneic Hematopoietic Cell Transplant Outcome. Seeking Greater Understanding the Pathogenesis of GVHD and Mortality

  • John A. Hansen

      Affiliations

    • Corresponding Author InformationCorrespondence and reprint requests: John A. Hansen, MD, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, D2-100, P.O. Box 19024, Seattle, WA 98109-1024.

The Fred Hutchinson Cancer Research Center and the University of Washington School of Medicine, Seattle, Washington

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Introduction 

Success following allogeneic hematopoietic cell transplantation (HSCT) is ultimately determined by the ability to achieve sustained engraftment and immune reconstitution, eradication of the abnormal or malignant cells responsible for the patient's disease, and control of graft-versus-host disease (GVHD). GVHD, an immune-mediated reaction initiated by donor T cells in response to host alloantigen, is the cause of significant morbidity and death in many patients. Genetic matching for HLA, the human major histocompatibility complex (MHC), located on chromosome 6p21, has for several years become well established as a requirement for optimal HSCT outcome [1]. Despite complete matching for all variation spanning 4 Mb of DNA across the MHC, acute GVHD (aGVHD), chronic GVHD (cGVHD), and transplant-related mortality (TRM) occurs in a significant number of HLA identical sibling donor transplants.

The Alloimmune Reaction 

Clinical GVHD results from an alloimmune reaction that occurs when immune competent donor T cells are transplanted to an immune compromised host and the genetic differences between donor and recipient are sufficient to induce T cell activation [2]. The genetic differences responsible for an allograft reaction encode polymorphic cellular proteins called histocompatibility antigens [3]. The strongest histocompatibility antigens are encoded by the class I and class II genes of the MHC, or HLA, but there are many other genes located throughout the genome that encode cellular peptides capable of generating significant alloimmune responses if variation in the gene product can be detected by T cells. These “allo” peptides are called minor histocompatibility antigens (mHA) [4]. Although HLA identical siblings share 50% of their genome, the mHA disparity is sufficient to cause clinically significant aGVHD in 30% to 40% of cases. Despite HLA matching among unrelated donor-recipient pairs, disparity for non-MHC mHA is greater because the recipient and donor do not share the same parental chromosomes [5].

Pathogenesis of GVHD 

The incidence, severity, and duration of GVHD following HSCT vary substantially from patient to patient 6, 7, 8, 9, 10, 11. Differences in GVHD phenotype can result from both inherited and clinical or environmental factors including type of disease, disease status, treatment history, HLA match, age, sex of donor and patient (and sex match), and the type of conditioning therapy administered prior to transplant 8, 12, 13.

High-dose cytotoxic conditioning can increase the risk of aGVHD by causing mucosal injury, which facilitates translocation of endotoxin into the bloodstream, suppressing T cell and natural killer (NK) cell-mediated allograft resistance and activating antigen-presenting cells (APCs) in the recipient. Within hours after transplantation, GVHD begins with the presentation of alloantigens by host dendritic cells, followed by activation of donor T cells, which undergo clonal expansion and migration into various lymphoid organs and target tissues [14]. The antihost alloimmune reaction is largely driven by the leakage of lipopolysaccharide (LPS) across the gut wall [15], and further amplified by multiple components of the immune systems, including NK cells, monocytes, macrophages, and proinflammatory cytokines 16, 17, 18, 19, 20.

Proteomic Analysis of aGVHD and TRM 

Several studies have described changes in plasma proteins that correlate with the risk of aGVHD, cGVHD, and TRM (summarized in Table 1). Although there are common discoveries among several of these studies, there are also findings that have not independently replicated, and for this reason true positives have not been clearly defined. There remains a great need for further and rigorously conducted studies that achieve both validation and also identification of the clinical covariables that it must be known to fully interpret and reliably implement biomarker data, both proteomic and genomic, into clinical risk assessment algorithms and preemptive therapies.

Table 1. Summary of Published Changes in Plasma Proteins Associated with Acute GVHD, TRM, and Chronic GVHD∗
ProteinaGVHDTRMcGVHD
IL1-RN Liem et al. 1998 [54]
IL2RMiyamoto et al. 1996 [55]; Grimm et al. 1998 [56]; Foley et al. 1998 [57]; Nakamura et al. 2000 [58]; Visentainer et al. 2003 [59]; Shaiegan et al. 2006 [60]; Paczesny et al. 2008 [61] Liem et al. 1998 [54]; Fujii et al. 2008 [62]
IL-6Imamura et al. 1994 [63]
IL-8Uguccioni et al. 1993 [64]; Paczesny et al. 2008 [61]Schots et al. 2003 [65]
IL-10Liem et al. 1998 [54] Liem et al. 1998 [54]; Visentainer et al. 2003 [59]
IL-12Nakamura et al. 2000 [58]; Mohty et al. 2005 [66]
IL-15Sakata et al. 2001 [67]
IL-18Nakamura et al. 2000 [58]; Fujimori et al. 2000 [68]; Shaiegan et al. 2006 [60]; Luft et al. 2007 [69]
BAFF Fujii et al. 2008 [62]
CD13 Fujii et al. 2008 [62]
CCL8Hori et al. 2008 [70]
CXCL10Piper et al. 2007 [71]
HGFOkamoto et al. 2001 [72]; Paczesny et al. 2008 [61]
IFNGImamura et al. 1994 [63]; Nakamura et al. 2000 [58]
TNFHoller et al. 1990 [73]; Symington et al. 1990 [74]; Imamura et al. 1994 [63]
TNFROr 1996 et al. [75]; Kitko et al. 2008 [76]; Choi et al. 2008 [77]; Paczesny et al. 2008 [61]
Syndecan-1Seidel et al. 2003 [78]
anti-dsDNA Fujii et al. 2008 [62]

aGVHD indicates acute graft-versus-host disease; cGVHD, chronic graft-versus-host disease; TRM, transplant-related mortality.

∗Refer to original publication for additional details.

Genomic Analysis GVHD and TRM 

Several studies over the last 10 years have identified genetic polymorphisms associated with GVHD and TRM (summarized in Table 2). Initially, these investigations focused on well-known genes encoding proinflammatory or immune modulating cytokines including IL1A, IL1B, IL1RN, IL6, IL10, INFG, TGFB, and TNF 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34. Subsequent studies have examined additional genes for variation associated with HSCT outcomes including CTLA4, ESR1, IL2, IL7R, IL8, IL10RB, IL18, NOD2, and VDR 28, 35, 36, 37, 38, 39, 40, 41, 42, 43.

Table 2. Genetic Variation in Immune Response Genes Associated with Acute GVHD, TRM, and Chronic GVHD
GeneHSCT-Associated PhenotypeStudy Population (N)∗VNTR or SNPDiscovery and Supporting Reference(s)‡Investigators Reporting Nonsignificant Results‡
AliasLocationAllelesrs Number
CTLA4 (CD152)aGVHD and survivalMRD (536)+49 (d), CT60 (d)† A/G, G/Ars231775, rs3087243Perez-Garcia et al. 2007 [41]
cGVHD +49/GG A/Grs231775Azarian et al. 2007 [42]
ESR1aGVHDMRD (108)VNTR, PvuII and XbaIintron 1——Middleton et al. 2003 [35]
FASaGVHDMRD (160)−670 (p)promoterA/G—Mullighan et al. 2004 [29]
IFNGaGVHDMRD (49)VNTRintron 1na—Middleton et al. 1998 [21]
aGVHDMRD (100)874 T/A——Socie 2001 [23]
IL1AcGVHDMRD (115)−899, VNTRpromoter, intron 6C/T, allele 2— —Cullup et al. 2003 [27]—
aGVHD and TRMURD(426)−889promoterC/T——Mehta 2007 [34]
IL1BaGVHDMRD−511 (p)promoterT/Crs16944MacMillan et al. 2003[28]—
aGVHDMRD (570)−511 (p/d)promoterC/Trs16944—Lin 2003 [26]
IL1RNaGVHDMRD (99)VNTRintron 1—naCullup et al. 2001 [24]—
aGVHD and cGVHDMRD (107)VNTR (d)intron 2absence of allele ∗2—Rocha et al. 2002 [25]—
MRD (570)9261 (p/d)intron 1G/A448341—Lin 2003 [26]
IL2aGVHDURD (95)−333 (p)promoterT/Grs2069762MacMillan Transplant 2003 [43]—
IL6aGVHDMRD (160)−174 (d)promoterG/Crs1800795Mullighan et al. 2004 [29]—
aGVHDND (93)−174 (p/d)promoterG/Crs1800795Karabon et al. 2005 [31]—
cGVHD −174promoterG/Crs1800795Cavet et al. 1999 [22]—
cGVHDMRD (100)−174 (p)promoterG/C Socie et al. 2001 [23]—
aGVHD, cGVHD, TRMMRD (570)−174 (d)promoterG/Crs1800795—Lin 2003 [26]
IL7RTRMMURD (75)+1237(p)cSNPA/G—Shamim et al. 2006 [40]—
TRMMRD (100)+510,+1237,+2087,+3101cSNPsC/T,A/G,C/T,A/G——Shamim 2006 [40]
IL10aGVHDMRD (49)IL10G;§promoter——Middleton et al. 1998 [21]—
aGVHDMRD (144)IL10/−1082, IL10−1064§promoterA/G—Cavet et al. 1999 [22]—
aGVHDMRD (100)happromoterG-C-C—Socie et al. 2001 [23]—
aGVHDMRD (993)−592 (p) and hap (p)promoterC/A, A-T-A Lin et al. 2003 [26]—
aGVHDMRD (160)ATA hap(p)promoter —Mullighan 2004 [29]
cGVHDMRD (107)−1082∗G/G(p)promoterA/G—Rocha et al. 2002 [25]—
cGVHD ATA hap(p)promoter Mullighan et al. 2004 [29]—
TRMURD (182)IL10R2§-SNP hap (d)promoterG-C-C Keen et al. 2004 [30]—
IL10RBaGVHDMRD (993)c238 (d)exon Lin et al. 2005 [37]—
IL18SurvivalURD (157)GCG hap(p) Cardodo et al. 2004 [38]—
NOD2aGVHD and TRM SNP8, 12, 3intragenicG/A, G/C, insertionrs2066844, rs2066845, rs2066847Holler 2004, 2006 36, 39—
TNFaGVHDMRD (49)TNFd^, ∗∗ VNTRnaMiddleton et al. 1998 [21]
TRMMRD (144)TNFd∗∗ VNTRnaCavet et al. 1999 [22]
aGVHDMRD (100) MRD (570) MRD (160)−308 7promoterG/Ars1800629—Socie 2001 [23]; Lin 2003 [26]; Mullighan 2004 [29]
TRMURD (182)TNFd and −1031promoter: VNTR and SNPTNFd∗4/−1031∗C hap—Keen et al. 2004 [30]—
aGVHD & TRMMRD (160)488 7 Mullighan et al. 2004 [29]—
TNFRIIcGVHDMRD (104)codon 196exon 6T/G Stark et al. 2003 [79]—
VDRaGVHD and TRMMRD (88)VNTR (d)intron 8 Middleton et al. 2002 [80]—

aGVHD indicates acute graft-versus-host disease; cGVHD, chronic graft-versus-host disease; HCST, hematopoietic cell transplantation; VNTR, variable number tandum repeat; SNP, single nucleotide polymorphisms; TRM, transplant-related mortality.

∗Study population: MRD indicates HLA matched related donor; ND, not defined; URD, unrelated donor.

†p indicates patient; d, donor.

‡Refer to original publication(s) for additional details.

§IL10G and IL10R are a microsatellites located in and nearby the IL10 gene.

IL10 promoter region haplotype, positions: −1082/−819/−592.

^TNFd is a microsatellite in the TBF region.

∗∗MRD cases, because they are HLA identical, share the same TNF genotypes.

Unfortunately, the results of most of these single-center studies have not been independently validated by others in separate patient populations. Lack of validation or inconsistency in these results may be due largely to lack of statistical power because many of the original studies were based on relatively small numbers (<200-300 cases). Nevertheless, these results have been sufficiently compelling to warrant additional study. Comprehensive critical reviews of this research have been recently published 44, 45, and other current papers have addressed the potential impact of developments in genomic sciences and the opportunity for expanding HSCT outcomes research to genome-wide discovery 1, 46.

Genome-Wide Association Studies (GWAS) 

The remarkable development in recent years of methods and tools for the characterization of the entire human genome has dramatically broadened the opportunity for the genetic analysis of disease. The recent completion of the human genome map 47, 48 and the development of dense single nucleotide polymorphism (SNP) marker maps of the genome 49, 50, as well as development of massively parallel genotyping technologies 51, 52, 53, have made it possible to screen genes in an unbiased manner for polymorphisms that correlate with any well-defined phenotype, disease status, or relevant quantitative trait. This is particularly important when considering complex traits that characterize HCT complications and outcomes. Consideration of the entire genome in an unbiased fashion permits the discovery of genetic factors that would have never been considered otherwise.

State-of-the-Art Genomic and Proteomic Studies of GVHD and Mortality 

The 3 papers that follow this Introduction are summaries of the oral presentations that will be given during the Genomics and Proteomics Scientific Session of the 2009 BMT Tandem meetings. These papers are each timely progress reports of our emerging understanding of the pathogenesis of GVHD and TRM. The paper by Sophie Paczesny, Jamie Ferrara, and team provides model example of the rigorous 2-phase, discovery and validation, proteomic study of changes in plasma proteins associated with the development of aGVHD. The technology used for the discovery phase used an antibody array containing antibodies specific for 120 human proteins including acute phase reactants, cytokines, angiogenic factors, tumor markers, leukocyte adhesion molecules, and metalloproteinases and their inhibitors. The papers by Seishi Ogawa et al. and Jason Chien et al. describe preliminary discovery data from 2 of the first large whole genome scans performed on DNA from both recipient and donor as a comprehensive approach to examining genetic disparity and GVHD (Ogawa et al.), and the association of genetic variation with transplant outcomes including Gram-negative bacteremia and bronchiolitis obliterans.

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Acknowledgments 

This work was supported by grants from the National Institutes of Health AI33484, CA015704, CA18029, HL087690, and HL094260.

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PII: S1083-8791(08)01119-1

doi:10.1016/j.bbmt.2008.12.500

Biology of Blood and Marrow Transplantation
Volume 15, Issue 1, Supplement , Pages e1-e7, January 2009

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