Graft-versus-host disease primary prevention

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2]

Overview

Primary prevention focuses on interventions that inhibit the onset of a disease or condition before the disease or condition even occurs. Primary prevention of GvHD refers to prevention of GvHD in patients who will receive a stam cell transplant. Primary prevention is highly important because GvHD can have high morbidity and mortality once the disease begins, and treatments like corticosteroids have adverse effects which can futher contribute to morbidity and mortality. Thus, there is an strong effort by clinicians to prevent the onset of GvHD. There are a few primary prevention aspects for GvHD.

Primary Prevention

The following are strategies that have been used, or have been proposed in theory, for primary prevention of GvHD.

Methotrexate, cyclosporin A, tacrolimus and sirolimus are common drugs used for GVHD prophylaxis.

  • Methotrexate: This is an immunomodulatory agent that functions by inhibiting dihydrofolate reductase, which ultimately impairs the ability of T cells to replicate DNA and thus proliferate.[1] It is typically given on post-transplant days 1, 3, 6, and 11. Methotrexate levels need to be monitored after administration, as there can be hepatic and pulmonary toxicity if the dose is high.
  • Cyclosporine: This is a calcineurin inhibitor and functions by inhibiting nuclear factor of activated T cells (NFAT) dephosphorylation and activation. Adverse effects include gingival hyperplasia, renal dysfunction, and hypertension.
  • Tacrolimus: This is a calcineurin inhibitor and functions by inhibiting nuclear factor of activated T cells (NFAT) dephosphorylation and activation.
  • Sirolimus: This immunosuppressive agent acts via inhibition of mammalian target of rapamycin (mTOR), thus inhibiting downstream signal transduction mediators that eventually lead to transcription of proteins involved in cell cycle progression for T cells.[2] One downside of sirolimus for primary prevention is that there is a risk for thrombotic microangiopathy, which has resulted in some hesitancy by clinicians to use this medication in the preventative setting.[2]
  • Antimicrobials: These have been used for gastrointestinal decontamination. This is based on the concept that intestinal bacteria contribute to inflammation and immune activation.[3] It is known that mice who received stem cell transplant in microbe-free conditions were at lower risk for GvHD.[3] Ciprofloxacin is a commonly used antibiotic that serves a role in primary prevention of GvHD. Near-complete bacterial decontamination of the gut has been studied, but this strategy has not been completed validated.
  • DNA-based tissue typing: This allows for more precise HLA matching between donors and transplant patients, which has been proven to reduce the incidence and severity of GVHD and to increase long-term survival.[4].
  • T cell depletion: Graft-versus-host-disease can largely be avoided by performing a T cell depleted bone marrow transplant. Umbilical cord blood, for example, contains few T cells and thus confers a decreased risk for GvHD. However these types of transplants come at a cost of diminished graft-versus-tumor effect, greater risk of engraftment failure or cancer relapse[7], and general immunodeficiency, resulting in a patient more susceptible to viral, bacterial, and fungal infection. In a multi-center study, disease-free survival at 3 years was not different between T cell depleted and T cell replete transplants[8].
  • Cytokine suppression: Suppression of cytokine-mediated effects can prevent GvHD. It has been postulated that tumor necrosis factor (TNF), derived from T cells, is a major cytokine involved in the pathogenesis of GvHD. Thus, elimination of soluble TNF can be considered as a theoretic prevention strategy.[9] It has been shown that elimination of soluble TNF from donor T lymphocytes caused a delay in GvHD morbidity and mortality.[9] In theory, the use of neutralizing antibodies to TNF could be an important primary preventative strategy.
  • Gastrointestinal microbiome: Optimization of the gastrointestinal microbiome can prevent GvHD. It has been shown that abundance of Blautia (an intestinal bacteria) helps prevent gastrointestinal GvHD.[3] This observation is based on the concept that the intestinal microbiome plays a significant role in the pathophysiology of GvHD via inflammatory and immune activation. Persons undergoing stem cell transplant who had increased amount of Blautia developed less GvHD.[3]

References

  1. Rezvani AR, Storb RF (2012). "Prevention of graft-vs.-host disease". Expert Opin Pharmacother. 13 (12): 1737–50. doi:10.1517/14656566.2012.703652. PMC 3509175. PMID 22770714.
  2. 2.0 2.1 Pidala J, Kim J, Anasetti C (2009). "Sirolimus as primary treatment of acute graft-versus-host disease following allogeneic hematopoietic cell transplantation". Biol Blood Marrow Transplant. 15 (7): 881–5. doi:10.1016/j.bbmt.2009.03.020. PMC 4856158. PMID 19539221.
  3. 3.0 3.1 3.2 3.3 Jenq RR, Taur Y, Devlin SM, Ponce DM, Goldberg JD, Ahr KF; et al. (2015). "Intestinal Blautia Is Associated with Reduced Death from Graft-versus-Host Disease". Biol Blood Marrow Transplant. 21 (8): 1373–83. doi:10.1016/j.bbmt.2015.04.016. PMC 4516127. PMID 25977230.
  4. Morishima Y, Sasazuki T, Inoko H; et al. (2002). "The clinical significance of human leukocyte antigen (HLA) allele compatibility in patients receiving a marrow transplant from serologically HLA-A, HLA-B, and HLA-DR matched unrelated donors". Blood. 99 (11): 4200–6. PMID 12010826.
  5. Grewal SS, Barker JN, Davies SM, Wagner JE (2003). "Unrelated donor hematopoietic cell transplantation: marrow or umbilical cord blood?". Blood. 101 (11): 4233–44. doi:10.1182/blood-2002-08-2510. PMID 12522002.
  6. Laughlin MJ, Barker J, Bambach B; et al. (2001). "Hematopoietic engraftment and survival in adult recipients of umbilical-cord blood from unrelated donors". N. Engl. J. Med. 344 (24): 1815–22. PMID 11407342.
  7. Hale G, Waldmann H (1994). "Control of graft-versus-host disease and graft rejection by T cell depletion of donor and recipient with Campath-1 antibodies. Results of matched sibling transplants for malignant diseases". Bone Marrow Transplant. 13 (5): 597–611. PMID 8054913.
  8. Lancet 2005 Aug 27-Sep 2;366(9487):733-41
  9. 9.0 9.1 Borsotti C, Franklin AR, Lu SX, Kim TD, Smith OM, Suh D; et al. (2007). "Absence of donor T-cell-derived soluble TNF decreases graft-versus-host disease without impairing graft-versus-tumor activity". Blood. 110 (2): 783–6. doi:10.1182/blood-2006-10-054510. PMC 1924485. PMID 17395784.



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