Hypo-reactive immune response
Hypo-reactive immune response
Time pression is used as GVHD prophylaxis after myeloablative transplant, moderate to severe acute GVHD (grades II-IV) occurs in 25% to 60% of matched related donor transplant recipients and up to 45% to 70% in unrelated donor recipients. Development of grade II-IV acute GVHD is associated with decreased survival in patients after allogeneic BMT.140-143
Chronic GVHD has a later onset than acute GVHD and is often clinically distinct.144 Chronic GVHD may resemble an autoimmune collagen vascular disease. Patients can manifest sclerodermatous skin changes, keratoconjunctivitis, sicca syndrome, lichenoid oral mucosal lesions, esophageal and vaginal strictures, liver disease, and pulmonary insufficiency. Despite immunosuppresive agents, approximately 30% to 50% of patients develop chronic GVHD after conventional myeloablative HLA-identical sibling BMT. The incidence of chronic GVHD may be even higher after allo-geneic transplantation using unmanipulated peripheral blood stem cells.45,46,51,52 Chronic GVHD may be classified as sub-clinical or clinical, limited or extensive. Although subclinical or clinically limited chronic GVHD often resolves spontaneously with minimal intervention, extensive chronic GVHD requires prolonged immunosuppressive treatment and is associated with significant morbidity and mortality. More than 50% of patients with extensive chronic GVHD will die, mostly secondary to infections resulting from severe immune dysfunction.
Large single-institution and registry series have identified factors that place patients at higher risk for the development of GVHD. For acute GVHD, these include HLA incompatibility, use of an unrelated donor, prior donor allosensitization through pregnancy or blood transfusion, older patient or donor age, recipient CMV seropositivity, and increased intensity of the ablative regimen. For chronic GVHD, prior acute GVHD is the major risk factor, but also important are use of peripheral blood stem cells, histoincompatibility, and the prior use of corticosteroids.95,145-147
The pathophysiology of GVHD has received extensive attention. It is recognized that donor T cells are critical mediators in the graft-versus-host reaction. However, recent animal research suggests that the pathophysiology of acute GVHD is far more complex and that it involves intricate interactions between cellular and cytokine components of the immune system (Figure 6.3).148,149 Acute GVHD is now believed to occur in three phases: (1) tissue damage from conditioning regimen, (2) donor T-cell activation phase, and (3) inflammatory effector phase. In the earliest phase of GVHD, inflammatory cytokines are released from host tissue in response to damage by the pretransplant conditioning regimen. These cytokines, including interleukin 1 (IL-1) and tumor necrosis factor-alpha, upregulate the expression of adhesion molecules and host major histocompatibility complex (MHC) antigens and enhance recognition of the host tissue by mature donor T lymphocytes. During the second phase, donor T cells of the T-helper 1 (Th1) subset are activated upon recognition of alloantigens and secrete cytokines such as interleukin 2 and interferon-alpha. IL-2 plays a central role in the recruitment of other T cells, cytotoxic T lymphocytes (CTLs), natural killer (NK) cells, monocytes, and macrophages.
T cells remain the prime target for most current therapeutic strategies in GVHD prophylaxis in humans. Effective approaches for the prevention and treatment of GVHD involve direct blockade of T-cell function. These methods have included the downregulation of T lymphocytes by inhibiting cellular proliferation (methotrexate), inhibition of de novo purine synthesis (mycophenolate mofetil), suppression of IL-2 secretion by blocking calcineurin activity (cyclosporine, tacrolimus), interfering with downstream growth signaling pathways (rapamycin), reduction of T-cell responsiveness by blocking the IL-2 receptor (dacluzimab), and generation of immunosuppressive cytokines (extracorporeal photopheresis).150-156 Combination therapy with methotrexate and a calcineurin inhibitor, albeit flawed, remains the gold standard for GVHD prophylaxis.157-160 The recent combination of tacrolimus and sirilimus (rapamycin) has shown significant promise in recipients of HLA-matched unrelated and related transplants.161
The most effective means for GVHD prophylaxis has been ex vivo depletion of T cells from the donor inoculum.162 Donor T-cell depletion (TCD), when it was first introduced in the early 1980s, offered the potential for prevention of GVHD without the morbidity associated with immunosuppressive drugs such as methotrexate and cyclosporine. Numerous TCD methods have been utilized over the past two decades; these have included negative selection techniques using monoclonal antibody(ies) plus complement, immunotoxins, counter-flow centrifugal elutriation, soybean lectin agglutination, and, more recently, positive selection through CD34+ columns.163-166 Most early trials documented that TCD could substantially limit acute and chronic GVHD. However, this reduction in GVHD did not translate into improved overall survival because of unexpected high rates of graft failure, Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (EBV-LPD), and disease recurrence following TCD-BMT (Table 6.3).167-170 It is believed that certain sets of donor cells removed in the purging process are also important for graft maintenance, viral surveillance, and elimination of residual leukemia cells that have survived the high-dose ablative conditioning regimen. Despite the problems associated with T-cell depletion, there remains great interest in developing and improving this technology, particularly for recipients of mismatched or unrelated grafts. Reasonable applications for TCD may include those patients at high risk for GVHD (unrelated or mismatched grafts) or patients with comorbid medical conditions who might have a high risk of complications after conventional BMT. TCD may be ideal for patients with diseases where GVL activity is less critical, such as first remission acute leukemia. In the future, studies need to assess the potential role of T-cell depletion when mobilized PBSCs are used for allogeneic transplantation, particularly with respect to its effect on chronic GVHD. It would be ideal to be able to manipulate different lymphoid subgroups responsible for GVHD and GVL, but whether these processes can be effectively separated at a clinical level remains unknown.
Once established, administration of corticosteroids is the most effective approach to the treatment of both acute and chronic GVHD. Complete responses occur in 25% to 40% of patients. Addition of other agents to corticosteroids or increasing the steroid dose has not improved response rates or outcomes.171,172 A comparative trial of 2 and 10mg/kg/day of methylprednisolone demonstrated no advantage of the higher dose in terms of response or survival.173 For acute GVHD, calcineurin inhibitors such as cyclosporine and tacrolimus are useful in patients who did not receive these agents initially as prophylaxis.174 Serotherapy with antithy-mocyte globulin (ATG) can produce responses, although subsequent infection rates are high and survival does not appear to be improved. Other anti-T-cell antibodies with distinct specficities have been studied. Responses have been reported, but these antibodies have not proven superior to steroids alone. Medications aimed at blocking T-cell proliferation (mycophenxlate mofetil) or activation (rapamycin) appear to induce responses in single-arm trials, but these agents have not yet been studied fully in randomized trials. Targeting cytokine receptors such as IL-2 (dacluzimab, denileukin difitox), IL-1 (IL-1RA), and tumor necrosis factor-alpha (TNF-a) (infliximab) have yielded promising results in small uncontrolled trials but have not proven to add benefit in randomized trials 150-156,175,176
Treatment of extensive chronic GVHD with immuno-suppressive therapy has been even less rewarding than that of acute GVHD. Although the combination of cyclosporine and prednisone is the treatment of choice in many centers, a recent randomized trial failed to show any survival advan-tage.177 Encouraging uncontrolled trials with thalidomide have been reported, but subsequent randomized studies did not demonstrate significant benefit.178,179 Both psoralen plus ultraviolet A (PUVA) therapy and extracorporeal photophere-sis (ECP) have been reported to be effective in acute and particularly chronic GVHD.180,181 Randomized studies are currently under way to evaluate the value of ECP. The overall disappointing results of immunosuppressive therapy for chronic GVHD make other efforts, such as prevention of infection and physical therapy, even more critical to maintenance of patient well-being.
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