Cord blood transplantation without host preconditioning: will there be GVHD?
The possibility of using cord blood in absence of host preconditioning would open up the door for a multitude of stem cell therapeutic applications. The currently dogma amongst cord blood transplanters is that administration of allogeneic cord blood, even if HLA-matched, would in the best case scenario lead to immunologically-mediated rejection or the graft, and in the worst case cause GVHD. Here we provide rationale for the preliminary clinical exploration of cord blood administration in a non-preconditioned host.
ABO-matched, HLA-mismatched transfusions
In the 1930s it was reported that cord blood could be safely used as a substitute for peripheral blood for performing transfusions [49]. Since HLA-matching was not available at that time and no adverse effects were noted, the feasibility of cord blood administration to a non-preconditioned host was suggested. A more recent Lancet publication described the use of cord blood as a source of blood donation for malaria infested regions in Africa. 128 pediatric patients with severe anemia needing transfusions were transplanted with an average of 85 ml of ABO matched cord blood with no HLA matching. No report of graft versus host was noted, and cord blood was proposed as a transfusion source when peripheral blood is not available due to economical or social reasons [50]. An extensive review of 129 patients transplanted with a total of 413 Units of cord blood (average 86 ml) with no preconditioning or HLA matching between 1999 to 2004 was published by Bhattacharya [51]. Of these patients, aged 2–86 years old and suffering from advanced cancer (56.58%) and other diseases (43.42%) such as ankylosing spondylitis, lupus erythematosus, rheumatoid arthritis, aplastic anemia, and thalassemia major, no immunological reactions were noted in patients followed for 1–4 years. The same author reported other patient cohorts that have been similarly treated and had no GVHD or other immune reactions [52-55]. Furthermore, transfusion of cord blood in non-HLA matched recipients was also associated with transient increases in peripheral CD34 counts, without evidence of GVHD in patients with cancer and HIV [56,57]. Unfortunately in these studies did not perform long-term molecular analysis for chimerism. Despite this drawback, it is evident from the initial work in the 1930s, to the numerous cases reported by Bhattacharya, to the publication in Lancet, that administration of cord blood is a safe procedure not associated with immunological consequences. Thus based on the current data, the worse a cord blood transplant will do is do nothing.
Administration of adult lymphocytes does not elicit GVHD
The cells that are "dangerous" from the cord blood from a GVHD perspective are lymphocytes that may have alloreactive potential. Lymphocytes from cord blood, in contrast to adult blood, are generally immature and usually do not secrete as many inflammatory cytokines. Therefore administration of allogeneic lymphocytes purified from adult blood would be a much more dangerous procedure, at least as far as GVHD is concerned, in contrast to administration of lymphocytes from cord blood. The fact is administration of lymphocytes from paternal sources has been performed in numerous reports in the clinical practice of using "paternal lymphocyte immunotherapy" for treatment of spontaneous abortions. Numerous trials have been conducted administering doses of up to 2 × 109 paternal lymphocytes into pregnant mothers who have had recurrent miscarriages [58,59]. These doses are higher than the 1.5–3 × 107 nucleated cells/kg administered during a cord blood transplant [60]. Interestingly, in pregnant women administered these high doses of completely allogeneic cells, no GVHD has ever been observed, although Th2 immune deviation has been reported by some groups [61,62]. Thus according to the current evidence, there is no fear of GVHD being induced after cord blood transplant. Bhattacharya even administered as many as 32 units of cord blood to an individual without seeing GVHD [57].
Homeostatic proliferation in lymphopenic environment causes GVHD
The reader will ask, in response to the above arguments regarding GVHD-inducing ability of cord blood, "why is GVHD, a clinical reality in patients receiving cord blood for hematological malignancies?" The answer is that current day cord blood transplants take place following ablation of host T cells. This creation of an "empty compartment" allows for homeostatic expansion of the newly introduced T cells, which primes them for aggressive immune reactions and alleviates their requirement for costimulation [63]. It is known from the transplantation literature that T cells reconstituting a host that has been lymphoablated are resistant to costimulatory blockade and tolerance induction [64]. Furthermore, the pioneering experiments of Rosenberg's group demonstrated that infusion of tumor specific lymphocytes following ablation of the recipient T cells, using conditions similar to those used in cord blood transplant preconditioning allows for highly aggressive anti-tumor responses that otherwise would not be observed [65]. Further supporting the concept that reconstitution of a lymphocyte deficient immune system can cause immune hyperreactivity comes from clinical observations of "autologous GVHD" in patients administered drugs associated with induction of lymphopenia [66,67]. We therefore propose that GVHD is not an intrinsic property of the allogeneic cells introduced into the host, but a result of the lymphoablation induced in the recipient prior to cellular administration.
Answers to all your Biology Questions
