Biology of Blood and Marrow Transplantation
Volume 12, Issue 5 , Pages 566-572, May 2006

Altered Functional Status of the Hypothalamic Dopaminergic Tone in Patients with Chronic Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation: A Pilot Study

  • Adalberto Parra

      Affiliations

    • Department of Endocrinology, Instituto Nacional de Perinatología, Mexico City, Mexico
    • ,
  • Jorge Ramírez-Peredo

      Affiliations

    • Department of Rheumatology, Instituto Nacional de Perinatología, Mexico City, Mexico
    • ,
  • Rocío Hidalgo

      Affiliations

    • Department of Endocrinology, Instituto Nacional de Perinatología, Mexico City, Mexico
    • ,
  • Amelia Morales-Toquero

      Affiliations

    • Laboratorios Clínicos de Puebla, Mexico City, Mexico
    • Centro de Hematología y Medicina Interna de Puebla, Mexico City, Mexico
    • ,
  • Gabriela Velásquez-Ramírez

      Affiliations

    • Laboratorios Clínicos de Puebla, Mexico City, Mexico
    • ,
  • Alejandro Ruiz-Argüelles

      Affiliations

    • Laboratorios Clínicos de Puebla, Mexico City, Mexico
    • ,
  • Guillermo J. Ruiz-Argüelles

      Affiliations

    • Laboratorios Clínicos de Puebla, Mexico City, Mexico
    • Centro de Hematología y Medicina Interna de Puebla, Mexico City, Mexico
    • Corresponding Author InformationCorrespondence and reprint requests: Guillermo J. Ruiz-Argüelles, MD, FACP, FRCP (Glasg), Centro de Hematología y Medicina Interna de Puebla, 8B Sur 3710, 72530 Puebla, PUE, Mexico

Received 17 October 2005; accepted 16 December 2005.

Article Outline

Abstract 

We compared the functional status of the hypothalamic dopaminergic tone in patients given an allogeneic hematopoietic stem cell transplantation (allo-HSCT) with chronic graft-versus-host disease (GVHD) with that observed in patients with allo-HSCT without chronic GVHD and in healthy controls. The effect of acute dopaminergic blockade with intravenous metoclopramide on serum prolactin (PRL) concentrations was evaluated. Twenty volunteers, 20 to 52 years of age, seronegative for both hepatitis C virus and the human immunodeficiency virus, were studied: (1) 10 clinically healthy men (group 1), and (2) 9 patients with leukemia, and 1 patient with refractory aplastic anemia who underwent allo-HSCT, 5 of whom (3 men and 2 women) developed chronic GVHD (group 2), and 5 (3 men and 2 women) who did not develop chronic GVHD (group 3). Serum PRL concentrations were measured both fasting and after intravenous administration of metoclopramide (10-mg bolus). The area under the PRL curve was calculated. Patients in group 2 were older than those in groups 1 and 3 (P < .018), but their body mass index was similar. Fasting serum PRL concentrations were similar among the 3 groups; however, group 2 had higher PRL concentrations throughout the test (P < .001) and a greater area under the PRL curve than groups 1 and 3 (P < .001), without differences between the last 2 groups. The differences remained significant after adjustment for age (P < .01). Our results in a small group of patients with chronic GVHD after allo-HSCT suggest the existence of an increased functional level of their hypothalamic dopamine tone, which would favor a tendency toward a diminished endogenous production, release of pituitary PRL, or both. This could represent an adaptive mechanism aiming to maintain circulating PRL concentrations within a physiological range.

Key words:  Dopaminergic tone , Graft-versus-host disease , Hematopoietic stem cell transplantation , Prolactin

 

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Introduction 

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a valid treatment for a number of malignant and nonmalignant bone marrow disorders [1, 2]. Graft-versus-host disease (GVHD) complicates nearly 50% of allo-HSCTs, and several factors are known to be associated and correlated with the development of GVHD in patients undergoing allo-HSCT and might thus be of use to anticipate the development of GVHD, thus allowing early modification of immunosuppressive therapy [3]. GVHD has been arbitrarily separated into 2 entities according to its occurrence after the allograft: acute and chronic GVHD [4], with a predominance of a T-helper type 1 (Th1) cytokine pattern in the former and a switch toward a Th2 cytokine profile in the latter [4, 5]. Although much has been learned about the immunobiology of GVHD, the precise etiopathogenic mechanisms remain largely unknown.

A previous article described increased serum prolactin (PRL) concentrations in humans after allogeneic bone marrow transplantation for hematologic malignancy or aplastic anemia complicated by chronic GVHD (beyond day 100 after grafting) [6]. Plasma PRL levels have also been found to be increased in women during conditioning and within 30 days after autologous blood stem cell transplantation for breast cancer [7]. It is interesting to note that PRL levels were higher in women who remained in continuous complete remission than in those with only a partial remission or ensuing early relapse [7].

These findings are particularly relevant because PRL—whether of pituitary or extrapituitary origin [8]—has long been recognized as a potent Th1 type cytokine that functions as a comitogen with interleukin 2 in the activation and proliferation of T cells and natural killer cells [9, 10, 11], particularly if PRL concentrations are within a physiological range [9]. Furthermore, early animal experiments suggested that PRL also participates in the humoral autoimmune response [12, 13] and this confirmed in humans with autoimmune diseases such as systemic lupus erythematosus [14, 15]. Thus, there is strong evidence to support its key role in the immunomodulation of both the humoral and cellular immune responses in humans [11, 16, 17, 18]. However, it must be kept in mind that “either too much, or too little PRL may be immunosuppressive” [11], particularly if the condition is sustained [9, 16]. Despite this knowledge, the information available on PRL and GVHD after allo-HSCT is scanty.

PRL also has been implicated in the restoration of the hematopoietic homeostasis under conditions of dysregulation, but not under normal steady-state conditions [19]. Furthermore, recombinant human PRL has been shown to stimulate lymphoid and myeloid reconstitution and/or promote hematopoiesis in different preclinical models [19, 20, 21].

Under physiological conditions, the pituitary release of PRL is mainly controlled by a tonic inhibitory mechanism mediated by dopamine (DA) [22]. Both basal serum PRL concentrations and its response to the intravenous administration of a DA-blocking agent, such as metoclopramide, have been considered a good index for evaluating the functional status of the hypothalamic dopaminergic tone in different clinical conditions [23, 24, 25]. However, the mechanisms controlling the extrapituitary production of PRL, specifically in lymphocytes, are largely unknown [26]. Nevertheless, PRL as an immune cell–derived cytokine can be “exported” in biologically significant amounts to the general circulation under special conditions [27] and exert its effects at the cellular level as an autocrine, paracrine, or endocrine factor [9, 16]. On the basis of this information, we aimed to compare the functional status of the hypothalamic dopaminergic tone in patients with allo-HSCT and chronic GVHD with that observed in patients with allo-HSCT without chronic GVHD and in healthy controls.

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Materials and methods 

The study protocol was approved by the Internal Review Board and the Human Ethical Committee of the Centro de Hematología y Medicina Interna de Puebla (Puebla, Mexico), and written informed consent was obtained from all volunteers. The study was conducted according to the Declaration of Helsinki (as amended October 2000).

Study Population 

The study encompassed 20 volunteers aged 20 to 52 years with a body mass index (BMI) between 20.6 and 32.9 kg/m2. None drank alcohol regularly or regularly ingested any medication known to increase serum PRL concentrations [28] 4 months before the study. All volunteers were clinically euthyroid and had normal fasting serum concentrations of thyrotropin (reference values, 0.3-4.2 μU/mL), free thyroxine (reference values, 0.8-2.0 ng/dL), and PRL (reference values, <20 ng/mL). All individuals were seronegative for both hepatitis C virus and the human immunodeficiency virus. The volunteers were classified into 2 categories: (1) 10 clinically healthy men (group 1) and (2) 9 consecutive patients with leukemia and 1 patient with severe refractory aplastic anemia who underwent allo-HSCT, 5 of whom (3 men and 2 women) developed chronic GVHD (group 2) and 5 of whom (3 men and 2 women) did not develop GVHD (group 3). Five patients were allografted for chronic myelogenous leukemia: 2 for acute myelogenous leukemia, 2 for acute lymphoblastic leukemia, and 1 for severe refractory aplastic anemia (Table 1).

Table 1. Clinical and Relevant Hematologic Data in Healthy Volunteers (Group 1) and in Patients with Leukemia and Bone Marrow Transplantation with (Group 2) and Without Graft-versus-Host Disease (Group 3)
GroupSexAge (y)BMI (kg/m2)CD34+ (×106/kg)Diagnosis
Group 1 (controls)
1M4824.9——
2M3422.1——
3M2020.6——
4M2322.4——
5M2425.9——
6M2221.7——
7M2724.6——
8M2225.7——
9M2622——
10M2627.2——
Group 2 (GVHD+)
1M2026.74.1CML
2M2331.71.9ALL
3M4531.85.9CML
4F3022.59.2CML
5F2627.217.7CML
Group 3 (GVHD−)
1M5127.76.9CML
2M5026.40.07⁎AML
3M3921.12.4AML
4F2520.31.2ALL
5F5232.98.4AA

BMI indicates body mass index; CML, chronic myelogenous leukemia; ALL, acute lymphoblastic leukemia; AML, acute myelogenous leukemia; AA, aplastic anemia.

⁎ Umbilical cord source.

Patients and Donors 

All the patients allografted in the Centro de Hematología y Medicina Interna de Puebla were prospectively accrued onto the study. Class I and II HLA antigens were studied by molecular biology. All patients with acute leukemia underwent transplantation in complete remission and had a Karnofsky status of 100% when the procedure was performed. The donor was an HLA-compatible (5/6 or 6/6) sibling in all instances.

Hematopoietic Stem Cell Mobilization and Apheresis 

Granulocyte colony-stimulating factor (10 μg/kg/d) was delivered to the sibling donors on days −5 to +2. The apheresis procedures were performed on days 0, +1, and +2, according to the cell counts, by means of a Haemonetics V-50 PLUS machine (Haemonetics Corporation, Braintree, MA) or a Baxter C-3000 PLUS machine (Baxter Healthcare, Deerfield, IL) by using the Spin-Nebraska protocol [29]. A total of 5000 to 7000 mL/m2 of blood was processed in each of the apheresis procedures to obtain a minimum of 5 × 108 mononuclear cells and/or 2 to 6 × 106 viable CD34 cells per kilogram of the recipient. Enumeration of the total white blood, mononuclear, and CD34+ cells was performed by flow cytometry [30, 31]. No purging procedure was performed.

Conditioning and Grafting 

The Mexican nonablative stem cell transplantation conditioning regimen was used [32, 33, 34, 35]: it is a simplification of the low-intensity conditioning regimens used in Houston [36] and in Jerusalem [37]. Oral busulfan 4 mg/kg was delivered on days −6 and −5; intravenous cyclophosphamide 350 mg/m2, on days −4, −3, and −2; and intravenous fludarabine 30 mg/m2, on days −4, −3, and −2. Oral cyclosporin A (CsA) 5 mg/kg was started on day −1, and intravenous methotrexate 5 mg/m2 was delivered on days +1, +3, +5, and +11. Oral CsA was continued through day 100, with adjustments according to the levels of whole-blood CsA; it was then tapered over 30 to 60 days. The products of the peripheral blood stem cell apheresis were reinfused on an outpatient basis on days 0 to 2, according to the CD34 cell yield. In one case (group 3; case 2), umbilical cord blood cells were used instead of peripheral blood stem cells. Acute and chronic GVHD were defined according to conventional criteria: chronic GVHD was defined as that appearing after day 100 [4, 38].

Chimerism Studies 

In cases with a sex mismatch, a fluorescent in situ hybridization technique was performed to demonstrate the X and Y chromosomes [39, 40], whereas restriction fragment length polymorphism [40, 41] studies in the peripheral blood lymphocytes were used in the other cases.

Experimental Protocol 

All individuals were studied identically. Between 8:00 and 8:30 am and after a 10- to 12-hour overnight fast, an indwelling catheter was placed in a forearm vein and kept patent with a slow intravenous drip of 0.15 mol/L NaCl solution. After a 30-minute rest, 3 basal nonheparinized blood samples were obtained at 15-minute intervals (−30, −15, and 0 minutes) and thereafter at 30, 60, 90, 120, and 180 minutes after a 10-mg intravenous bolus of metoclopramide (Carnotprim; Laboratorios Carnot, Mexico City, Mexico). At each sampling time, the first 0.3 mL of blood was discarded to avoid a dilution error, and all subjects were closely monitored for extrapyramidal symptoms. Physical activity of any kind, smoking, or sleeping was not allowed throughout the test. Blood samples were centrifuged at 3000 rpm, and the serum was kept frozen at −20°C until duplicate determinations of PRL were performed. In previous studies in a different population of patients [42], we found that the early PRL response (0-180 minutes) to metoclopramide gave the same but qualitatively better information compared with the overall response over a period of 5 hours. The serum PRL concentrations at −30, −15, and 0 minutes in each patient were pooled and expressed as mean fasting serum PRL concentration. The area under the PRL curve (AUC-PRL) was calculated by using a trapezoidal model [43].

Hormonal Assays 

PRL determinations were performed in duplicate by using commercially available immunoradiometric kits (Diagnostic Products Corporation, Los Angeles, CA), and the intra-assay and interassay coefficients of variation for PRL concentrations <30 ng/mL were 7% and 8.1%, respectively. For concentrations between 31 to 300 ng/mL, they were 6.2% and 7.8%, respectively. PRL kits have been calibrated against the World Health Organization 3rd International Reference Standard Preparation. Serum samples were tested in 3 assays, and the samples were distributed equally relative to each group studied. The sensitivity of the assay was 1.8 ng/mL.

Statistical Analysis 

Between-groups differences for age, BMI, mean fasting serum PRL concentrations, and AUC-PRL were analyzed by analysis of variance, and ex post facto differences were analyzed with the Tukey test. Serum PRL concentrations during the intravenous metoclopramide were evaluated for both intragroup and intergroup differences by using analysis of variance for repeated measures. When differences between groups were found, a secondary analysis was performed that adjusted for age. The statistical analysis was performed with SPSS Windows version 11.0 (SPSS Inc., Chicago, IL). A P value ≤.05 was considered significant.

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Results 

All patients engrafted successfully. Of the patients who developed chronic GVHD, only 1 (patient 1) had had previous acute GVHD. The chimerism studies showed that all patients became full chimeras after the allograft. Four cases of chronic GVHD were limited forms of the condition, whereas 1 was extensive (patient 2); all patients had cutaneous forms of GVHD, and 1 had liver damage. There were no instances of neural forms of GVHD. Three patients (cases 1, 2, and 3) were given low doses of corticosteroids (prednisone 5 mg/d). After achieving remission, patient 2 had a severe relapse of chronic GVHD with progressive cholestasis; he was treated unsuccessfully with both intravenous prednisolone and anti-CD52 monoclonal antibody but died 182 days after the allograft and 65 days after the metoclopramide test. The rest of the patients are alive in complete remission.

During the metoclopramide test, none of the volunteers experienced any side effects, including extrapyramidal symptoms, as the result of an exaggerated sensitivity to the DA antagonist used. Chronologic age was similar in groups 1 and 2 but was significantly lower than in group 3 (P < .018). No differences in BMI were detected among the 3 groups (Table 1).

Fasting PRL serum concentrations were similar among the 3 groups, both at each individual basal time and as the mean basal concentration (Figure 1). In response to metoclopramide, there was a sharp and significant increase in serum PRL concentrations within 30 minutes (P < .001) and a subsequent steady decline until the end of the test in the 3 groups. However, the magnitude of the PRL response was significantly greater in group 2 than in groups 1 and 3 throughout the test (P < .001), without significant differences between the last 2 groups. After adjustment for age, the responses in serum PRL concentrations remained significantly different when comparing group 2 versus groups 1 and 3 (P < .01). There were no significant sex differences in the serum PRL response to metoclopramide among the 3 groups (P = .796).

  • View full-size image.
  • Figure 1. 

    Mean basal serum prolactin concentration and that in response to a 10-mg intravenous bolus of metoclopramide (MCP) in a group of 10 healthy controls, in 5 allografted patients with chronic GVHD, and in 5 allografted patients without GVHD. Values represent the mean ± SEM.

The AUC-PRL was greater in group 2 (mean, 11 914.0 ng/mL/180 min; 95% confidence interval, 10 614.6-13 213.3 ng/mL/180 min) than in group 1 (mean, 5932.8 ng/mL/180 min; 95% confidence interval, 4695.8-7169.7 ng/mL/180 min) and group 3 (mean, 5676.4 ng/mL/180 min; 95% confidence interval, 5804.6-8923.4 ng/mL/180 min; P < .001). No significant differences were found between groups 1 and 3. Furthermore, individual analysis showed that the highest AUC-PRL value in groups 1 and 3 was below the lowest individual value in group 2 (Figure 2). In other words, there was no discernible overlapping of individual values. There was no correlation between the AUC-PRL and the number of allogeneic CD34 cells grafted in the patients.

  • View full-size image.
  • Figure 2. 

    Individual values for the area under the prolactin curve during the intravenous metoclopramide test in a group of 10 healthy controls, in 5 allografted patients with chronic GVHD, and in 5 allografted patients without GVHD.

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Discussion 

In this study we demonstrated, in a small group of patients who underwent allo-HSCT and later developed chronic GVHD, a clearly augmented serum PRL response during acute DA blockade with metoclopramide compared with the same type of patients who did not develop chronic GVHD and compared with clinically healthy individuals. There were no significant differences among the last 2 types of individuals. Consequently, this study offers evidence on the existence of an increased functional level of hypothalamic DA tone in patients with chronic GVHD after allo-HSCT, which, acting in concert with hypothalamic and/or intrapituitary signals, would favor a tendency toward a diminished pituitary PRL release and/or production [22, 23, 42]. This variance in the PRL responsiveness to metoclopramide could be due to a hypothalamic or pituitary cause, because it may differ according to the DA levels in the hypophyseal portal circulation or to the level of sensitivity of the lactotrophs to DA [22].

The clear difference in PRL response between patients with chronic GVHD, patients without GVHD, and clinically healthy individuals could not be ascribed to a drug effect because no patient was taking any drug known to influence PRL secretion [28]. The possible influence of an excessive BMI (>30 kg/m2) in 2 patients of group 2 also cannot explain the difference observed, because obesity is associated with a decreased PRL response to metoclopramide [44]. Furthermore, most of the volunteers (18 of 20) had a BMI between 20 and 27 kg/m2, considered a normal range [45]. Sex differences seem not to explain the variance in PRL response either, inasmuch as there were 2 women in group 2 (GVHD+) and also 2 women in group 3 (GVHD−), and their individual responses lay within those observed for men in the 3 groups (P = .798). Furthermore, the PRL response to metoclopramide is similar during both the follicular and luteal phases of the menstrual cycle [46].

A drawback of our study is the small number of patients studied; nevertheless, the differences in the results were clear and highly significant, and no individual overlapping was observed in the AUC-PRL values between patients with and without GVHD. A similar increase in the functional level of the hypothalamic DA tone has been recently described in women with systemic lupus erythematosus, along with an augmented secretion and release of bioactive lymphocyte-derived PRL aiming to maintain serum PRL concentrations within a physiological range, probably as a contribution to downregulate the humoral autoimmune milieu in these patients [47]. Thus, our finding may also have biological relevance. We hypothesize that our patients with chronic GVHD were in a Th2 status similar to that found in some autoimmune diseases, in which high serum PRL concentrations contribute to the acceleration of autoantibody production and, thus, may become deleterious [48, 49, 50]. Indeed, others have found increased fasting serum PRL levels in larger series of patients with chronic GVHD [6], although we did not observe this, most likely because of the small number of patients studied. Therefore, the increased functional level of the hypothalamic tone in these patients with chronic GVHD may represent an adaptive or counterregulatory mechanism attempting to maintain the endogenous production and/or release of PRL—whether of pituitary or lymphocyte origin—within a physiological range. Whether or not this adaptation influences the excessive autoimmune response already present in these patients [4, 5, 38] cannot be disclosed from this study.

There is a pressing need for new approaches in the treatment and prevention of the GVHD reaction, whether acute or chronic, and there is evidence that PRL plays an as-yet unrecognized role in the pathogenesis of GVHD in humans [6, 7].

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Acknowledgments 

We are indebted to Esther Casanueva, PhD, for her assistance in the statistical analysis.

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PII: S1083-8791(05)01418-7

doi:10.1016/j.bbmt.2005.12.035

Biology of Blood and Marrow Transplantation
Volume 12, Issue 5 , Pages 566-572, May 2006

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