Allogeneic Hsct In Recentonset Autoimmune Type 1 Diabetes Mellitus

In contrast to autologous HSCT, allogeneic HSCT may cure autoimmunity, and consequently preserve remaining pancreatic islets in patients with recent-onset type 1 diabetes. The rationale for allogeneic HSCT for patients with recent-onset type 1 diabetes is based on the following observations: (1) allogeneic HSCT will halt autoimmune-mediated destruction of islet p cells; (2) preservation of intact islet p cells is beneficial to the patient even in the absence of full metabolic control; (3) because hyperglycemia is more easily managed in patients with functional islet p cells, chronic complications are less likely to develop; and (4) there is a low probability of disease relapse or recurrence after allogeneic HSCT.

Allogeneic HSCT is difficult to justify in recently diagnosed patients, however, because chronic effects of hyperglycemia are unlikely to manifest before complete loss of islet p cells. In patients likely to receive maximum therapeutic benefit from allogeneic HSCT, therefore, lack of life-threatening disease manifestations argues against high-risk, aggressive therapies. This conundrum is not unique to type 1 diabetes; for example, in patients with the congenital disease p-thalassemia, HSCT early in the course of disease (before peripheral organ involvement) results in a higher rate of disease-free survival, and a correspondingly lower incidence of transplant-related mortality (approximately 3% in patients younger than age 16) (44). The potential benefit of allogeneic HSCT differs, however, with respect to the indicating disease. In patients with type 1 diabetes, potential therapeutic benefit of relief from hyperglycemia and associated chronic complications must be balanced against the risks associated with allogeneic HSCT.

Donor selection will increase the comparable risk of allogeneic HSCT for early-onset type 1 diabetes. Although the incidence of type 1 diabetes in the general population of Western countries is approximately 1 in 300, the incidence for first-degree relatives of affected individuals is approximately 1 in 20 (45).

The strongest genetic determinants of type 1 diabetes are particular polymorphisms of the MHC class II DQ and DR alleles; approximately 20-50% of familial aggregation is associated with specific DQ and DR haplotypes (45). Because genetic susceptibility to the development of type 1 diabetes is associated with MHC loci, allogeneic HSCT from an HLA-identical sibling donor might not correct genetic susceptibility to the development of autoimmunity. Although genes outside the MHC complex may influence genetic susceptibility to the development of type 1 diabetes, these associations are unclear, and likely contributory rather than causal (18). Selection of a related donor with a disparate DQ or DR haplotype would correct genetic susceptibility toward development of type 1 diabetes; however, MHC class II DR or DQ loci disparity between donor and recipient is associated with an increased incidence of acute graft versus host disease following HSCT (46). Therefore, to correct genetic susceptibility, allogeneic HSCT would require at least a single loci donor-recipient mismatch, which is a negative indication for allogeneic HSCT in low-risk patients (47).

Although donor selection increases the risk of allogeneic HSCT in patients with recent-onset type 1 diabetes, the balance of risk versus benefit to HSCT still may be shifted in favor of HSCT. Identification of patients with increased risk for developing severe complications would increase the perceived benefit of allogeneic HSCT; for instance, specific genetic polymorphisms are associated with increased risk of proliferative retinopathy (48), nephropathy (49), and coronary heart disease (50). Furthermore, demonstration of islet regeneration and consequent resumption of full metabolic control after allogeneic HSCT would favor allogeneic HSCT. Although differentiation of donor hematopoietic stem cells into pancreatic islets is unlikely, allogeneic HSCT in mice led to homing and engraftment of donor bone marrow-derived endothelial cells in the exocrine pancreas (51). Increased angiogenesis may promote autologous islet regeneration, particularly if therapy with growth factors known to promote islet neogenesis were initiated after HSCT (52).

A concomitant decrease in risks associated with allogeneic HSCT likewise would favor clinical use of HSCT in patients with recent-onset type 1 diabetes. Nonmyeloablative HSCT reduces the toxicities of induction therapies, allows for recovery of autologous hematopoiesis in the event of graft loss, and preserves immunologic responsiveness to novel immune challenges (reviewed in ref. 8). In actively diabetic nonobese diabetic (NOD) mice, nonmyeloablative HSCT resulted in mixed donor-recipient hematopoietic chimerism that restored tolerance to autologous islet p cells (53). Similar observations of a graft-vs-autoim-munity effect after clinical transplantation would increase the potential benefit of HSCT. Additionally, ex vivo manipulation of donor grafts to induce recipient-specific tolerance and the potential for donor-specific immunotherapy in the event of recurrent p cell-specific autoimmune reactivity may further reduce the risks associated with allogeneic HSCT (reviewed in ref. 54). Finally, if allogeneic HSCT in patients with severe, life-threatening complications of chronic hyperglycemia successfully cured autoimmunity and demonstrated low risk of acute mortality, then these therapies could be extended to patients with recent-onset type 1 diabetes.

In summary, allogeneic HSCT before complete loss of pancreatic islets may cure type 1 diabetes, and the risks of HSCT may be justified in patients with acute, life-threatening hypoglycemic episodes or patients at increased risk of developing life-threatening complications of chronic hyperglycemia. Nevertheless, patients with recent onset type 1 diabetes are at low risk for immediate disease-related mortality, and thus HSCT with MHC class II DQ or DR mismatched donor grafts carries unacceptable risk with available therapies.

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