Graft-versus-host disease (GVHD), a common complication that is caused by donor T cells following allogeneic hematopoietic cell transplant. Recently, the functional state of T cells has been characterized by their chemokine receptor expression pattern (1). T cells expressing chemokine receptor CCR5 contribute to the rejection of solid organ allografts (2) and development of murine GVHD (3-5). A non-functional mutant allele of CCR5, CCR5Δ32, is found with 10% frequency in Caucasians (6-7). In a study of renal-transplant survival, patients homozygous for CCR5Δ32 had significantly prolonged graft survival compared to heterozygous or wild type patients (8). Here, we retrospectively compared outcomes among patients receiving marrow grafts from unrelated donors homozygous for CCR5Δ32 to those from donors expressing CCR5.
We screened the donor DNA repository at Fred Hutchinson Cancer Center for the CCR5Δ32 mutation by a PCR method (9). Among 1273 donors, 9 were homozygous for CCR5Δ32. Recipients of those bone marrow grafts were predominantly CML patients (CML=8 and AML=1), and we therefore decided to confine our study to the CML patient group. Patients were 18-50 years old and transplanted between 1988 to 2000. They received cyclophosphamide and fractionated total body irradiation, unmanipulated marrow, and GVHD prophylaxis with cyclosporine and methotrexate (9). A total of 344 CML patients had a CCR5 wild-type donor, 39 had a CCR5Δ32 heterozygous donor, and 8 had a CCR5Δ32 homozygous donor. Logistic regression model was used to assess the association between CCR5 genotype and acute GVHD, and Cox regression was used for chronic GVHD and relapse. As shown in Table 1, there was less GVHD among patients whose donor was CCR5Δ32 homozygous compared to patients with a wild-type or heterozygous donor, although most of the differences are not statistically significant. The number of patients with a homozygous donor is small, making it difficult to derive firm conclusions even where results are suggestive of a true difference. Moreover, there are several factors that impact GVHD, relapse, and mortality. With only 8 patients with a homozygous donor, we made limited adjustments. After controlling for severity of disease (categorized as low (chronic phase) vs. intermediate (accelerated phase or blast crisis in remission) vs. high (blast crisis), the effects associated with the homozygous group are similar to the unadjusted results (data not shown). Similarly, after adjusting for number of mismatched HLA alleles (considering HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1, with a range of 0 to 8 total mismatches in the 391 patients), the effects associated with the homozygous group are similar to the unadjusted results (data not shown).
Table 1.
| +/+ (n=344) | +/- (n=39) | -/- (n=8) | |
|---|---|---|---|
| Grades 2-4 | 309 (90%) OR=1 |
34 (87%) OR=0.77 (0.28-2.10, p=.61) |
6 (75%) OR=0.34 (0.07-1.75, p=.20) |
| Grades 3-4 | 124 (36%) OR=1 |
13 (33%) OR=0.89 (0.44-1.79, p=.74) |
1 (13%) OR=0.25 (0.03-2.08, p=.20) |
| Skin* | 288 (84%) OR=1 |
18 (46%) OR=0.89 (0.37-2.11, p=.79) |
4 (50%) OR=0.19 (0.05-0.80, p=.02) |
| Liver* | 159 (46%) OR=1 |
32 (82%) OR=0.65 (0.33-1.30, p=.22) |
2 (25%) OR=0.39 (0.08-1.95, p=.25) |
| Gut* | 219 (64%) OR=1 |
14 (36%) OR=0.82 (0.42-1.61, p=.57) |
5 (63%) OR=0.95 (0.22-4.05, p=.95) |
| Chronic** | 207 (60%) HR=1 |
19 (49%) HR=0.96 (0.60-1.53, p=.85) |
3 (38%) HR=0.45 (0.14-1.41, p=.17) |
| Relapse | 66 (19%) HR=1 |
9 (23%) HR=1.71 (0.85-3.43, p=.13) |
3 (38%) HR=1.80 (0.57-5.71, p=.32) |
| Mortality | 167 (49%) HR=1 |
24 (62%) HR=1.59 (1.04-2.44, p=.03) |
4 (50%) HR=1.01 (0.37-2.71, p=.99) |
organ-specific GVHD of any grade (1-4)
clinical extensive chronic GVHD
In summary, the absence of functional CCR5 in marrow donors may be associated with less GVHD. With only 8 patients having a homozygous donor, these preliminary results are in need of larger numbers. Therefore, we propose screening the sample repository from the National Marrow Donor Program Foundation to identify additional patients with a CCR5Δ32 homozygous donor. Currently CCR5 antagonists are developed and approved for HIV treatment (10). Further studies may provide rationale to develop novel treatment for GVHD.
Acknowledgments
This work is supported by grants CA18029 and CA15704 from the National Institutes of Health (NIH), Bethesda, MD.
Footnotes
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References
- 1.Luther SA, Cyster JG. Chemokines as regulators of T cell differentiation. Nat Immunol. 2001;2:102–107. doi: 10.1038/84205. [DOI] [PubMed] [Google Scholar]
- 2.Hancock WW. Chemokine receptor-dependent alloresponses. Immunol Rev. 2003;196:37–50. doi: 10.1046/j.1600-065x.2003.00084.x. [DOI] [PubMed] [Google Scholar]
- 3.Murai M, Yoneyama H, Harada A, Yi Z, Vestergaard C, Guo B, Suzuki K, Asakura H, Matsushima K. Related Active participation of CCR5+CD8+ T lymphocytes in the pathogenesis of liver injury in graft-versus-host disease. J Clin Invest. 1999;104:49–57. doi: 10.1172/JCI6642. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Serody JS, Burkett SE, Panoskaltsis-Mortari A, Ng-Cashin J, McMahon E, Matsushima GK, Lira SA, Cook DN, Blazar BR. T-lymphocyte production of macrophage inflammatory protein-1alpha is critical to the recruitment of CD8+ T cells to the liver, lung, and spleen during graft-versus-host disease. Blood. 2000;96:2973–2980. [PubMed] [Google Scholar]
- 5.Murai M, Yoneyama H, Ezaki T, Suematsu M, Terashima Y, Harada A, Hamada H, Asakura H, Ishikawa H, Matsushima K. Peyer’s patch is the essential site in initiating murine acute and lethal graft-versus-host reaction. Nat Immunol. 2003;4:154–160. doi: 10.1038/ni879. [DOI] [PubMed] [Google Scholar]
- 6.Smith MW, Dean M, Carrington M, Winkler C, Huttley GA, Lomb DA, Goedert JJ, O’Brien TR, Jacobson LP, Kaslow R, Buchbinder S, Vittinghoff E, Vlahov D, Hoots K, Hilgartner MW, O’Brien SJ. Contrasting genetic influence of CCR2 and CCR5 variants on HIV-1 infection and disease progression. Hemophilia Growth and Development Study (HGDS), Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC), ALIVE Study. Science. 1997;277:959–965. doi: 10.1126/science.277.5328.959. [DOI] [PubMed] [Google Scholar]
- 7.Smith MW, Dean M, Carrington M, Huttley GA, O’Brien SJ. CCR5-delta 32 gene deletion in HIV-1 infected patients. Lancet. 1997;350:741. doi: 10.1016/S0140-6736(05)63551-9. [DOI] [PubMed] [Google Scholar]
- 8.Fischereder M, Luckow B, Hocher B, Wuthrich RP, Rothenpieler U, Schneeberger H, Panzer U, Stahl RA, Hauser IA, Budde K, Neumayer H, Kramer BK, Land W, Schlondorff D. CC chemokine receptor 5 and renal-transplant survival. Lancet. 2001;357:1758–1761. doi: 10.1016/s0140-6736(00)04898-4. [DOI] [PubMed] [Google Scholar]
- 9.Hansen JA, Gooley TA, Martin PJ, Appelbaum F, Chauncey TR, Clift RA, Petersdorf EW, Radich J, Sanders JE, Storb RF, Sullivan KM, Anasetti C. Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia. N Engl J Med. 1998;338:962–968. doi: 10.1056/NEJM199804023381405. [DOI] [PubMed] [Google Scholar]
- 10.Dhami H, Fritz CE, Gankin B, Pak SH, Yi W, Seya MJ, Raffa RB, Nagar S. The chemokine system and CCR5 antagonists: potential in HIV treatment and other novel therapies. J Clin Pharm Ther. 2009;34:147–60. doi: 10.1111/j.1365-2710.2008.00978.x. [DOI] [PubMed] [Google Scholar]